GSK Clinical Study Register [PDF]

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure:  Information will be excluded in order to protect the privacy of patients and all named persons associated with the study  Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.  Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

CONFIDENTIAL CONFIDENTIAL

The GlaxoSmithKline group of companies

RM2008/00422/00 RM2008/00422/00 FFU111439

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Study Report Title:

A Randomized, Double-Blind, Placebo-Controlled, ParallelGroup, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR)

Phase:

IV

Compound Number: GW685698X; VERAMYST (Fluticasone Furoate) Effective Date:

10-NOV-2008

Description: The primary objective of this study was to compare the efficacy and safety of 4 weeks of treatment with intranasal fluticasone furoate (also known as GW685698X) 110 mcg once daily and placebo nasal spray in subjects ≥12 years of age with perennial allergic rhinitis. The study was conducted in Canada, Estonia, Germany, Hungary, the Russian Federation, Slovakia, and the US and included 315 randomized subjects. The primary efficacy measure for the study was the mean change from baseline over the entire treatment period in daily reflective total nasal symptom scores (rTNSS). Key secondary measures were the mean change from baseline over the entire treatment period in morning pre-dose instantaneous total nasal symptom scores (iTNSS) and the mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS). A health outcomes questionnaire, the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities (RQLQ[S]), was also administered. Other secondary measures were total and individual nasal symptom scores, total and individual ocular symptom scores, and peak nasal inspiratory flow (PNIF). Safety measures included adverse event reporting, routine laboratory tests (hematology and chemistry), vital signs (systolic and diastolic blood pressure, heart rate), physical examinations, and nasal examinations. Fluticasone furoate nasal spray 110 mcg was well tolerated over 4 weeks of treatment. The most common AE was epistaxis, reported by 15% of subjects in the fluticasone furoate 110 mcg group and 8% of subjects in the placebo group; all instances of epistaxis were mild in intensity. The results of this study support the once-daily use of fluticasone furoate 110 mcg nasal spray in adult and adolescent subjects 12 years of age and older for the treatment of symptoms of PAR. Subject: Perennial Allergic Rhinitis, fluticasone furoate nasal spray, GW685698X, Veramyst Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.

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CONFIDENTIAL CONFIDENTIAL

The GlaxoSmithKline group of companies

RM2008/00422/00 RM2008/00422/00 FFU111439

Authors:

Indication Studied: Perennial Allergic Rhinitis Initiation Date:

25 Jan 2008

Completion Date:

26 Jun 2008

Date of Report:

10 Nov 2008

Sponsor Signatory: (and Medical Officer)

MD Global Clinical Vice President Respiratory Medicine Development Center GlaxoSmithKline

This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents.

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TABLE OF CONTENTS Page

ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10

1. ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Subject Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE . . . . . .

12

3. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

4. STUDY OBJECTIVE(S). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14

5. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Overall Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Protocol Amendments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Inclusion/Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. Predetermined Criteria for Subject Withdrawal . . . . . . . . . . . . 5.4. Investigational Product(s). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. Description of Investigational Product(s) . . . . . . . . . . . . . . . . . 5.4.2. Dosages and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3. Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.4. Blinding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.7. Treatment of Investigational Product Overdose . . . . . . . . . . . . 5.4.8. Nasal Spray Malfunctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . 5.5.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.2. Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.3. Medical Device(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.4. Non-drug Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.1. Demographic and Baseline Assessments . . . . . . . . . . . . . . . . 5.6.2. Efficacy Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.3. Onset of Effect Assessment/Maximal Effect . . . . . . . . . . . . . .

14 15 17 18 18 23 24 24 24 25 25 25 26 26 26 26 26 26 27 27 28 28 28 31

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5.6.4. Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.5. Pharmacogenetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . 5.6.6. Health Outcomes Assessments . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8. Data Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.1. Timings of Planned Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.2. Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.3. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.4. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.5. General Considerations for Data Analyses . . . . . . . . . . . . . . . 5.8.6. Data Handling Conventions . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.7. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.8. Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.9. Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.10. Pharmacogenetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.11. Health Outcomes Analyses . . . . . . . . . . . . . . . . . . . . . . . . . .

31 36 36 37 39 39 39 39 40 40 41 41 41 42 42 42

6. STUDY POPULATION RESULTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Disposition of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Populations Analyzed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Demographics and Other Baseline Characteristics . . . . . . . . . . . . . . 6.4.1. Demographic Characteristics and Allergy History . . . . . . . . . . 6.4.2. Baseline Nasal and Ocular Symptoms. . . . . . . . . . . . . . . . . . . 6.4.3. Other Current Medical Conditions . . . . . . . . . . . . . . . . . . . . . . 6.5. Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.1. Concomitant Medications Taken During the Screening Period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.2. Concomitant Medications Taken During the Treatment Period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43 43 43 44 45 45 46 47 47

7. EFFICACY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Primary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Key Secondary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1. Mean Change from Baseline in AM Pre-dose iTNSS . . . . . . . 7.2.2. Mean Change from Baseline in Daily rTOSS . . . . . . . . . . . . . . 7.3. Secondary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.1. Total Nasal Symptom Scores. . . . . . . . . . . . . . . . . . . . . . . . . .

49 49 50 50 52 54 54

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7.3.2. Individual Nasal Symptom Scores . . . . . . . . . . . . . . . . . . . . . . 7.3.3. Total Ocular Symptom Scores . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.4. Individual Ocular Symptom Scores . . . . . . . . . . . . . . . . . . . . . 7.3.5. Peak Nasal Inspiratory Flow (PNIF) . . . . . . . . . . . . . . . . . . . . . 7.3.6. Onset of Treatment Effect and Time to Maximum Effect . . . . . 7.4. Subgroup Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.1. Summary of Primary Endpoint by Age . . . . . . . . . . . . . . . . . . . 7.4.2. Summary of Primary Endpoint by Country . . . . . . . . . . . . . . . . 7.5. Efficacy Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58 61 63 65 68 69 69 70 71

8. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.1. Screening Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.2. Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.3. Post-Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.4. Drug-related AEs During the Study Period . . . . . . . . . . . . . . . 8.3. Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.1. Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.2. Non-Fatal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Adverse Events Leading to Withdrawal from Study . . . . . . . . . . . . . . 8.5. Adverse Events by Age and Gender . . . . . . . . . . . . . . . . . . . . . . . . . 8.6. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.7. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.7.1. Laboratory Values Over Time . . . . . . . . . . . . . . . . . . . . . . . . . 8.7.2. Individual Subject Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.7.3. Abnormalities of Potential Clinical Concern . . . . . . . . . . . . . . . 8.8. Other Safety Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.8.1. Nasal Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.8.2. Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.9. Safety Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72 72 72 72 73 74 74 75 75 75 75 75 76 76 76 76 79 80 80 81 81

9. PHARMACOGENETIC RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

10. HEALTH OUTCOMES RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

11. DISCUSSION AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86 87

12. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

13. CASE NARRATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91

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STUDY POPULATION DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . .

94

EFFICACY DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . . . . .

433

SAFETY DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

701

HEALTH OUTCOME DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . . .

1431

ATTACHMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Attachment 1 - Report and Analysis Plan . . . . . . . . . . . . . . . . . . . . . . . . .

1442 1442

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LIST OF FIGURES Page

Figure 1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2 Mean Change from Baseline in Daily rTNSS over the Treatment Period (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3 Mean Change from Baseline in AM Pre-dose iTNSS over the Treatment Period (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4 Mean Change from Baseline in Daily rTOSS over the Treatment Period (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

15 50 52 54

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LIST OF TABLES Page

Table 1 Time and Events Schedule. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 2 Treatment Lot Numbers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 3 Laboratory Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 4 Subject Accountability (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . Table 5 Protocol Deviations (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . Table 6 Demographic and Baseline Characteristics (ITT Population). . . . . . . Table 7 Baseline TNSS, Nasal Congestion Scores, and TOSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 8 Treatment Compliance (ITT Population) . . . . . . . . . . . . . . . . . . . . . . Table 9 Daily rTNSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 10 AM Pre-dose iTNSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . Table 11 Daily rTOSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 12 AM rTNSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 13 PM rTNSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 14 Daily rTNSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 15 AM Pre-dose iTNSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . Table 16 Daily Reflective Individual Nasal Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population) . . . . . . . . . . . . . . . . . . . . Table 17 AM Pre-dose Instantaneous Individual Nasal Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population) . . . . . . . Table 18 AM Pre-dose iTOSS (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . Table 19 Daily Reflective Individual Ocular Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population) . . . . . . . . . . . . . . Table 20 AM Pre-dose Instantaneous Individual Ocular Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population) . . . . . . . Table 21 Daily PNIF (L/min; ITT Population). . . . . . . . . . . . . . . . . . . . . . . . . . Table 22 AM PNIF (L/min; ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 23 PM PNIF (L/min; ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 24 Change from Baseline in Daily rTNSS by Age Category (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 25 Change from Baseline in Daily rTNSS by Country (ITT Population) Table 26 Extent of Exposure to Study Medication (ITT Population) . . . . . . . . Table 27 AEs Occurring at Greater than or Equal to 1% Incidence and More Common than Placebo (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . Table 28 Drug-related AEs (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . .

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17 24 35 43 44 45 47 48 49 51 53 55 56 57 58 59 60 62 64 65 66 67 68 70 70 72 73 74

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Table 29 Laboratory Shifts from Baseline to Endpoint – Hematology (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 30 Laboratory Shifts from Baseline to Endpoint – Clinical Chemistry (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 31 Nasal Examination Shifts from Baseline to Endpoint (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 32 Baseline, Endpoint and LS Mean Change from Baseline to Endpoint for RQLQ(S) Scores (ITT Population) . . . . . . . . . . . . . . . . . . . .

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Abbreviations AE ALT AM ANCOVA ATC bpm CI C-PAP CRF DNA ECG eCRFs FDA GCP GCSP GSK ICH IEC IgE iTNSS iTOSS ITT IRB IUD IUS IVRS LS Mcg MedDRA OTC PAR PGx PIN PM PNIF PRIST QC RAP RAMOS RAST RBC RQLQ[S] rTNSS rTOSS

Adverse event Alanine aminotransferase Ante Meridiem (before midday) Analysis of covariance Anatomical Therapeutic Classification Beats per minute Confidence interval Continuous positive airway pressure Case report form Deoxyribonucleic acid Electrocardiogram Electronic case report forms Food and Drug Administration Good clinical practices Global Clinical Safety and Pharmacovigilance GlaxoSmithKline International Conference on Harmonization Independent ethics committee Immunoglobulin E Instantaneous total nasal symptom score Instantaneous total ocular symptom score Intent to treat Institutional review board Intrauterine device Intrauterine system Interactive Voice Response System Least squares Micrograms Medical Dictionary for Regulatory Activities Over-the-counter Perennial allergic rhinitis Pharmacogenetics Personal identification number Post Meridiem (after midday) Peak nasal inspiratory flow Paper RadioImmunosorbent Test Quality control Reporting analysis plan Registration and Medication Ordering System RadioAllergoSorbent Test Red blood cell Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities Reflective total nasal symptom score Reflective total ocular symptom score - 910 -

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SAE SAR SCA SE TNSS TOSS ULN US USAN WBC w/w

Serious adverse event Seasonal allergic rhinitis Standard clarification agreement Standard error Total nasal symptom score Total ocular symptom score Upper limit of normal United States United States Adopted Name White blood cell Weight per weight

Trademark Information Trademarks of the GlaxoSmithKline group of companies VERAMYST

Trademarks not owned by the GlaxoSmithKline group of companies Astelin In-Check Nasal InForm LogPad PRIST RAST SAS Xolair

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1.

ETHICS

1.1.

Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board.

1.2.

Ethical Conduct of the Study

This study was conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, and, the guiding principles of the Declaration of Helsinki.

1.3.

Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures at Visit 1 (Screening Visit). An appropriately signed and dated assent was obtained from the parents or guardian if the subject was a child under 18 years of age. Electronic case report forms (eCRFs) were provided for each subject’s data to be recorded.

2.

INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

A total of 34 investigational sites randomized subjects for this multicenter study: 12 in the United States (US), 10 in Canada, 3 in Germany, 3 in the Russian Federation, 3 in Hungary, 2 in Estonia, and 1 in Slovakia. Two additional investigators (one in Slovakia and one in Hungary) screened subjects (3 and 1, respectively) but did not randomize these subjects. One additional investigator (Slovakia) did not screen or randomize any subjects. The study was administered by the sponsor, GlaxoSmithKline. An independent data monitoring committee was not enlisted to evaluate study data. Central laboratory facilities were provided by Quest Laboratories.

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3.

INTRODUCTION

Rhinitis is defined as inflammation of the membranes lining the nose, characterized by nasal symptoms, including nasal itching, rhinorrhea, and/or nasal congestion [Settipane, 2001]. Allergic rhinitis is an immunoglobulin E (IgE)-mediated, inflammatory disorder of the upper airway that occurs following allergen exposure. Allergic rhinitis affects 20 to 40 million people in the US each year [Settipane, 2001]. Other studies have reported that the condition affects up to 30% of the population in other parts of the world, including Europe and Japan [Bousquet, 2001]. Nearly half of allergic rhinitis sufferers, which number 1 in 5 of the US population [NAEPP, 2007; Settipane, 1986], experience symptoms including nasal congestion, rhinorrhea, nasal itching, and associated symptoms of eye burning and eye itching during at least 4 months of the year [Foresi, 2000]. Perennial allergic rhinitis (PAR) is a type of allergic rhinitis that is triggered by allergens which are present year-round. The allergens responsible for PAR are commonly found in household environments and include animal dander from household pets, house dust mites, cockroach, and mold spores. Intranasal corticosteroids are highly effective medications for controlling the nasal symptoms that accompany allergic rhinitis. The importance of their place in treatment has been recognized by The American Academy of Allergy, Asthma, and Immunology, which now considers them first-line therapy when nasal congestion is a major component of the allergic rhinitis patient’s presentation [Dykewicz, 1998]. In support of this treatment guideline, a meta-analysis of 16 randomized, controlled trials also found intranasal corticosteroids significantly more effective at relieving nasal discharge, itch, and postnasal drip than oral antihistamines, the most prescribed treatment for allergic rhinitis [Weiner, 1998]. While the exact pharmacological mechanism of intranasal corticosteroids is unknown, these medications are known to reduce vascular permeability and edema of the nasal mucosa through inhibitory effects on inflammatory cells and mediator activity. Fluticasone furoate, the investigational drug for this study, is a novel corticosteroid with potent glucocorticoid activity administered in a unique, side-actuated device. As such, it has been shown to activate the glucocorticoid response element and inhibit proinflammatory transcription factors, such as nuclear factor κB (NF κB) [GlaxoSmithKline Document Number SH2002/00038/00], and antigen-induced lung eosinophilia in sensitized rats [GlaxoSmithKline Document Number SH2002/00044/00]. Fluticasone furoate has been shown to have low bioavailability (the absolute bioavailability of fluticasone furoate nasal spray in healthy volunteers is on average 0.50%) [Allen, 2007]. Fluticasone furoate is the adopted name by the USAN (United States Adopted Name) Council. Anti-inflammatory therapy is a well-accepted component of the management of rhinitis, and intranasal corticosteroids are among the preferred treatments for PAR. The protocol for this study was developed using current knowledge of the drug, current practice for treating allergic rhinitis, and is consistent with guidance provided by the Food and Drug

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Administration [Food and Drug Administration (FDA) Guidance for Industry, 2000] and the Committee for Medicinal Products for Human Use [CHMP, 2004]. As an objective measure of nasal airway patency and obstruction, peak nasal inspiratory flow (PNIF) rates were collected in this study. PNIF has been used to evaluate medical and non-medical therapies and has also been used as an outcome measure in nasal challenge testing [Wilson, 2003]. Data have shown the sensitivity of this test and the close correlation with patients’ symptoms of blockage and other objective measures of nasal airway function [Wilson, 2003]. Wilson et al [Wilson, 2000] demonstrated a significant correlation between improvements in nasal symptoms and peak inspiratory flow. In addition, PNIF measurements may aid in the assessment of subjects who have impaired symptom perception [Starling-Schwanz, 2005]. The PNIF has been found to be more discriminative than symptom scores in detecting efficacy differences between doses [Bende, 2002]. The safety and efficacy of fluticasone furoate nasal spray for the symptoms of seasonal and perennial allergic rhinitis have been demonstrated during the Phase 3 clinical development program. Fluticasone furoate nasal spray (tradename VERAMYST®) was first approved in April 2007 by the US Food and Drug Administration (FDA) for the treatment of symptoms of seasonal and perennial allergic rhinitis in adults and children ≥2 years [VERAMYST Prescribing Information, 2008]. The current PAR study was conducted to determine the efficacy of fluticasone furoate nasal spray for the treatment of ocular symptoms associated with PAR.

4.

STUDY OBJECTIVE(S)

The objective of this study was to compare the efficacy and safety of fluticasone furoate nasal spray 110 mcg once daily with vehicle placebo nasal spray in subjects with PAR, 12 years of age and older.

5.

INVESTIGATIONAL PLAN

This randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluated the efficacy and safety of once-daily, intranasal administration of fluticasone furoate nasal spray 110 mcg administered for 4 weeks in adult and adolescent subjects (12 years of age and older) with PAR. It was planned for 30 - 40 investigative sites in North America, Europe, and the Russian Federation to randomize 288 subjects. All subjects were outpatients.

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5.1.

Overall Study Design

Figure 1 illustrates the study schematic. Figure 1

Study Design

Subjects who satisfied the entry criteria entered a screening period (Visit 1) consisting of a minimum of 7 days and a maximum of 14 days. During the screening period, subjects scored their symptoms on an electronic diary (e-diary) in order to determine eligibility for randomization. After a minimum of 7 days, subjects who fulfilled the randomization criteria were randomly assigned in a 1:1 ratio to one of the following two intranasal, double-blind groups to self-administer treatment for 28 days (4 weeks): fluticasone furoate nasal spray 110 mcg once daily or placebo nasal spray once daily. The first dose of study drug was self-administered in the clinic prior to noon at Visit 2 by randomized subjects; thereafter, subjects were instructed to administer two sprays per nostril each morning. Subjects returned to the clinic each week for 4 weeks (Visits 3 to 6), based on the date of Visit 2 (Randomization), during the treatment period. All clinic visits were to be made within ±3 days of scheduled visits. The double-blind treatment period was not to exceed 32 days. Subjects were instructed not to take any antiallergy/anti-rhinitis medication during the screening or treatment study periods. No allergy rescue medication was allowed throughout the entire study period. During the 4-week treatment period, subjects rated their nasal and ocular symptoms of allergic rhinitis and recorded them on the e-diary. Subjects also documented study drug administration/compliance, PNIF readings, medical conditions experienced, and concomitant medications taken. At Visit 2 and the final visit (Visit 6/Early Withdrawal),

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subjects completed the health outcomes quality of life instrument (Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ(S)]). A follow-up telephone contact for adverse event (AE) assessment was made to the subject 3 to 5 days after the Visit 6/Early Withdrawal Visit to assess for any posttreatment adverse events. The Time and Events Schedule for this study is presented in Table 1.

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Table 1

Time and Events Schedule Visit Number 1

2

3

4

5

6

EWa

Phone Callb

Time Relative to Visit (Day) -14 to -7

1

Permitted Visit Window

8 ±3

15 ±3

22 ±3

29 ±3

32 +2

Time Relative to Visit (Week) -2 to -1

0

1

2

3

4

5

ACTIVITY Informed consent

X

PGx Informed consent Xc Subject number assignment X Medical history/disease history/Demographics X Concomitant medication assessment X X X X X X X Verification of inclusion/exclusion criteria X X Vital Signs and Physical Examination X X X Nasal examination X X X X X X X Skin testing (prick method) if not done within 12 months X of Visit 1) Clinical laboratory tests (hematology and chemistry) X X X 12-lead ECGs X Issue e-diary and review use for screening period X Dispense PNIF meter and face mask, review X instructions, and demonstrate proper use Adverse event assessment X X X X X X X Urine pregnancy test (all females of childbearing X X X X X potential) Randomization number assignment X RQLQ(S)d X X X Review use of e-diary for treatment period X Nasal spray technique demonstration X Dispense double-blind study drug to eligible subjects X Pharmacogenetic sampling X X Collect double-blind study drug X X Collect electronic diary, PNIF meter and face mask X X Compliance assessment X X X X X X a. Early Withdrawal b. Follow-up telephone call to subject was made within 3-5 days following Visit 6 or Early Withdrawal. c. The PGx informed consent was obtained anytime during the study but prior to taking the PGx blood sample. d. The RQLQ(S) was completed at the beginning of the visit.

5.2.

Protocol Amendments

The protocol was amended once (07 January 2008) to correct the compound number on page 1 of the protocol and to correct the EudraCT Number on the Sponsor Information Page (page 3 of the protocol).

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5.3.

Selection of Study Population

Subjects with a diagnosis of PAR who met inclusion criteria were randomized. The study was stratified by country and was centrally randomized within each country. 5.3.1.

Inclusion/Exclusion Criteria

Subjects were randomized into the study if they provided written informed consent, a medical history that included PAR, and if they met the inclusion/exclusion/randomization criteria for the study. These criteria were selected to ensure that otherwise healthy, symptomatic subjects with perennial allergic rhinitis would be enrolled in the study. The inclusion/exclusion and randomization criteria were as follows: Inclusion Criteria

Subjects were eligible for inclusion in this study only if all of the following criteria applied: 1.

Informed consent •

2.

Outpatient •

3.

4.

Subject had provided an appropriately signed and dated informed consent. An appropriately signed and dated assent must have been obtained from the parents or guardian if the subject was a child under 18 years of age. Subject was treatable on an outpatient basis.

Age •

≥12 years at Visit 2

•

≥18 years at Visit 1 for Russia and Germany

Male or eligible female Female subjects were not enrolled if they planned to become pregnant during the time of study participation. A urine pregnancy test was performed for all females of childbearing potential at Visits 1, 2, 5, and Visit 6/Early Withdrawal. To be eligible for entry into the study, females of childbearing potential must have committed to the consistent and correct use of an acceptable method of birth control, as defined by the following: •

Abstinence

Females of childbearing potential who were not sexually active committed to complete abstinence from intercourse for 2 weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of 6 days). •

Oral contraceptive (either combined estrogen/progestin or progestin only)

•

Injectable progestogen

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5.

•

Implants of levonorgestrel

•

Percutaneous contraceptive patches

•

Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year

•

Male partner who was sterile (vasectomy with documentation of azospermia) prior to the female subject’s entry into the study and was the sole sexual partner for that female subject

•

Double barrier method – condom or occlusive cap (diaphragm or cervical /vault caps) plus spermicide

•

Estrogenic vaginal ring

Diagnosis of PAR to include: •

A positive skin test (by prick method) response to appropriate perennial allergen (house dust mites, animal dander, mold, or cockroach,) within last 12 months prior to Visit 1 or at Visit 1. A positive skin test was defined as a wheal ≥3 mm larger than the diluent control for prick testing.

•

Two-year medical history and past treatment of PAR (written or verbal confirmation) which included perennial, i.e., year-round symptoms. PAR symptoms included nasal congestion, rhinorrhea, nasal itching and sneezing, eye itching/burning, eye tearing/watering, and eye redness.

In vitro tests for specific IgE (such as RadioAllergoSorbent Test [RAST], Paper RadioImmunoSorbent Test [PRIST]) were not allowed for the diagnosis of PAR. NOTE: Subjects who met the above criteria for PAR and who also had a history of allergy to a seasonal pollen that was present in their geographic area during study participation were NOT eligible for randomization. 6.

Environment •

7.

Ability to comply with study procedures •

8.

Subject must have been symptomatic to appropriate perennial allergen (animal dander, house dust mites, cockroach, mold) and willing to maintain same environment throughout the study. Subject understood and was willing, able and likely to comply with study procedures and restrictions.

Literate •

Subject was able to read, comprehend, and record information in English or native language.

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Randomization Criteria

At Visit 2, subjects must have met the following criteria: 1. Average of the last 8 rTNSS assessments (4 AM assessments, 4 PM assessments) over the four 24-hour periods prior to randomization were ≥6. This included the AM assessment on the morning of the randomization visit, 2. Average of the last 8 reflective nasal symptom assessments for nasal congestion (4 AM assessments, 4 PM assessments) over the four 24-hour periods prior to randomization were ≥2. This included the AM assessment on the morning of the randomization visit. 3. Average of the last eight rTOSS assessments (4 AM assessments, 4 PM assessments) over the four 24-hour periods prior to randomization were ≥4. This included the AM assessment on the morning of the randomization visit. 4. The subject demonstrated the ability to comply with the use of the daily e-diary, defined as completion of at least 80% of the assessments during the screening period. Exclusion Criteria

Subjects were not eligible for inclusion in this study if any of the following criteria applied: 1. Significant concomitant medical conditions, defined as but not limited to: •

a historical or current evidence of clinically significant uncontrolled disease of any body system (e.g., tuberculosis, psychological disorders, eczema). Significant was defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or which would confound the interpretation of the study results if the disease/condition exacerbated during the study

•

a severe physical obstruction of the nose (e.g., deviated septum or nasal polyp) or nasal septal perforation that could affect the deposition of double blind intranasal study drug

•

nasal (e.g., nasal septum) or ocular injury or surgery in the last 3 months

•

asthma, with the exception of mild intermittent asthma [Asthma Education and Prevention Program Guidelines [NAEPP, 2007; GINA, 2006], or very mild asthma (Canada) [Lemiére, 2004]. NOTE: Subjects were allowed to use shortacting inhaled beta2 agonists ONLY on an as needed basis.

•

rhinitis medicamentosa

•

bacterial or viral infection (e.g., common cold) of the eyes or upper respiratory tract within 2 weeks of Visit 1 or during the screening period

•

documented evidence of acute or significant chronic sinusitis, as determined by the individual investigator

•

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•

current cataract

•

physical impairment that would affect subject’s ability to participate safely and fully in the study

•

clinical evidence of a Candida infection of the nose

•

history of psychiatric disease, intellectual deficiency, poor motivation, substance abuse (including drug and alcohol) or other conditions that would limit the validity of informed consent or that would confound the interpretation of the study results

•

history of adrenal insufficiency.

2. Use of corticosteroids, defined as: •

Intranasal corticosteroid within 4 weeks prior to Visit 1

•

Inhaled, oral, intramuscular, intravenous, ocular, and/or dermatological corticosteroid (with the exception of hydrocortisone cream/ointment, 1% or less or equivalent) within 8 weeks prior to Visit 1.

3. Use of other allergy medications within the timeframe indicated relative to Visit 1 •

Intranasal or ocular cromolyn within 14 days prior to Visit 1

•

Short-acting prescription and non-prescription antihistamines, including ocular preparations and antihistamines contained in insomnia and “nighttime” pain formulations taken for insomnia, within 3 days prior to Visit 1

•

Long-acting antihistamines within 10 days prior to Visit 1: including loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, terfenadine

•

Long-acting antihistamine, astemizole, within 12 weeks prior to Visit 1

•

Intranasal antihistamines (e.g., Astelin) within 2 weeks prior to Visit 1

•

Oral or intranasal decongestants within 3 days prior to Visit 1

•

Long-acting beta-agonists within 3 days prior to Visit 1

•

Intranasal, oral, or inhaled anticholinergics within 3 days prior to Visit 1

•

Histamine H2-receptor antagonists including cimetidine, ranitidine, famotidine, nizatidine within 1 day prior to Visit 1

•

Oral antileukotrienes within 3 days prior to Visit 1

•

Subcutaneous omalizumab within 5 months of Visit 1

•

Subjects were not permitted to use any artificial tears, eyewashes/nasal irrigation solutions, homeopathic preparations, lubricants, sympathomimetic, or vasoconstrictor preparations during the screening and treatment periods. No exclusion period prior to screening (Visit 1) was required for these treatments.

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4. Use of other medications that could affect allergic rhinitis or its symptoms •

Chronic use of concomitant medications, such as tricyclic antidepressants, that would affect assessment of the effectiveness of the study drug

•

Use of other intranasally administered medications

5. Use of immunosuppressive medications 8 weeks prior to screening and during the study 6. Immunotherapy Subjects receiving immunotherapy could be enrolled into the study if the immunotherapy was not initiated within 30 days of Visit 1, if the dose remained fixed over the 30 days prior to Visit 1, and the dose remained fixed for the duration of the study. 7. Use of any medications that significantly alter the pharmacokinetics of fluticasone furoate, including ritonavir and ketoconazole 8. Allergy/Intolerance •

Known hypersensitivity to corticosteroids or any excipients in the product

9. Use of contact lenses 10. Use of Nasal Continuous Positive Airway Pressure (C-PAP) device (mask or pillow) 11. Clinical trial/experimental medication experience •

Participation in a clinical trial within 12 months prior to Visit 1

•

Participation in a previous or current fluticasone furoate nasal spray (GW685698X) clinical study

12. Positive pregnancy test or female who was breastfeeding •

Had a positive or inconclusive pregnancy test at Visit 1 or Visit 2

13. Affiliation with investigational site •

Subject was a participating investigator, sub-investigator, study co-ordinator, or employee of a participating investigator, or was an immediate family member of the aforementioned.

14. Current tobacco use •

Subject was currently using, or had used within the past year, smoking products including cigarettes, cigars, and pipe or chewing tobacco.

15. Chickenpox or measles •

A subject was not eligible if he/she currently had chickenpox or measles, or had been exposed to chickenpox or measles during the last three weeks and was nonimmune. If a subject developed chickenpox or measles during the study, he/she was withdrawn from the study. If a non-immune subject was exposed to chickenpox or measles during the study, his/her continuation in the study was at the discretion of the investigator, taking into consideration the likelihood of developing active disease. - 2122 -

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16. Findings of a clinically significant, abnormal electrocardiogram (ECG) 17. Findings of a clinically significant laboratory abnormality 5.3.2.

Predetermined Criteria for Subject Withdrawal

5.3.2.1.

Subject withdrawal from the investigational product

Premature discontinuation of the study drug was defined as discontinuation of the study drug for more than 2 consecutive days before the end of the study period. Subjects who discontinued administration of study drug prematurely were withdrawn from the study. 5.3.2.2.

Subject withdrawal from the study

A subject who took double-blinded study drug but withdrew prior to Visit 6 had withdrawn early. Subjects who withdrew early were not replaced. Subject withdrawal from the study was required and Early Withdrawal procedures were to be performed, when: •

a subject was significantly non-compliant with the requirements of the protocol

•

a subject had not completed the 4-week treatment period

•

a subject became pregnant

•

a subject had an adverse event that would, in the investigator’s judgment, make continued participation in the study an unacceptable risk

•

the treatment blind was broken for a subject (by other than GSK Global Clinical Safety and Pharmacovigilance [GCSP] personnel)

•

a subject developed chickenpox or measles

•

a subject met the following liver chemistry threshold stopping criteria: Alanine aminotransferase (ALT) ≥3xUpper Limit of Normal (ULN) and bilirubin ≥1.5xULN (>35% direct). ALT ≥5xULN. ALT ≥3xULN if associated with the appearance or worsening of hepatitis symptoms or rash.

•

GlaxoSmithKline discontinued the study.

A subject could voluntarily discontinue participation in this study at any time. The investigator could also, at his or her discretion, discontinue the subject from participating in this study at any time. If a subject was prematurely discontinued from participation in the study for any reason, the investigator was to make every effort to perform an Early Withdrawal visit.

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Any clinically significant adverse event, laboratory test, nasal examination, or clinically significant unfavorable change observed during the Early Withdrawal Visit necessitated that the subject be followed or treated until satisfactory resolution occurred. In the event that a subject was prematurely discontinued from the study at any time due to an AE or SAE, the procedures stated in the protocol for AEs/SAEs were to be followed.

5.4.

Investigational Product(s)

5.4.1.

Description of Investigational Product(s)

GlaxoSmithKline manufactured all study medication. Fluticasone furoate nasal spray was manufactured as a preserved, aqueous suspension containing 0.05% w/w of micronized fluticasone furoate. The preservative system consists of benzalkonium chloride and disodium edetate. Each nasal spray bottle contained a volume of suspension sufficient to deliver a minimum of 120 actuations. Each spray of the suspension contained approximately 27.5 mcg of fluticasone furoate. The matching placebo nasal spray was comprised only of the fluticasone furoate vehicle. Batch information is provided in Table 2. Table 2

Treatment Lot Numbers

Treatment Fluticasone furoate nasal spray Vehicle placebo nasal spray

Batch Number

To ensure proper functioning, spray devices were primed according to the Subject Instruction Leaflet. Demonstration devices were also made available to allow site staff to demonstrate proper administration. 5.4.2.

Dosages and Administration

At the entry to the double-blind treatment period (Visit 2), eligible subjects were assigned to blinded, intranasal study treatment in accordance with the randomization schedule. Each eligible subject was randomized to one of the two double-blind treatment groups: fluticasone furoate 110 mcg once daily or placebo nasal spray once daily. Subjects were educated in the use of the nasal spray using a placebo demonstration device. The Subject Instruction Leaflet was reviewed with the subjects and given to them for reference during the study. Subjects were instructed to administer two sprays per nostril once daily each morning. Administration of the dose was performed by alternately spraying one spray to each nostril followed by a second spray to each nostril. The first dose of study drug was selfadministered by the subjects before noon in the clinic at Visit 2. Subjects were instructed to administer study drug each morning for 4 weeks following their pre-dose nasal and ocular symptom assessments and PNIF assessments.

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5.4.3.

Dose Rationale

Fluticasone furoate nasal spray has been approved for use in the treatment of symptoms of seasonal and PAR in adults and children ≥2 years. Fluticasone furoate 110 mcg once daily is the recommended starting dose for patients 12 years of age and older [VERAMYST Prescribing Information, 2008]. 5.4.4.

Blinding

The 4-week treatment period for this study was double-blind. All investigators, subjects, and GlaxoSmithKline personnel remained blinded. At Visit 2, a study nasal spray device was dispensed to each randomized subject. Each nasal spray device was labelled with double-blinded labels. The contents of the label met all applicable regulatory requirements. Only in the case of an emergency, when knowledge of the investigational product was essential for the clinical management or welfare of the subject, the investigator could unblind a subject’s treatment assignment. If the blind was broken for any reason, the investigator was instructed to notify GSK immediately of the unblinding incident without revealing the subject’s study treatment assignment. In addition, the investigator was instructed to record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate data collection tool. If a serious adverse event was reported to GSK, GCSP staff could also unblind the treatment assignment for the individual subject. If an expedited regulatory report to one or more regulatory agencies was required, the report would identify the subject’s treatment assignment. When applicable, a copy of the regulatory report may be sent to investigators in accordance with relevant regulations, GSK policy, or both. If a subject’s treatment code was unblinded, the subject had to be withdrawn from the study. 5.4.5.

Treatment Assignment

Eligible subjects were randomly assigned to study treatment, in accordance with a GSK computer-generated, randomization schedule. The treatment assignment was made via an Interactive Voice Response System (IVRS) called Registration and Medication Ordering System (RAMOS) and accessed via personal identification numbers (PIN) assigned to authorized site personnel. The randomization number assignment by RAMOS corresponded with a medication treatment kit. Once assigned, the kit and randomization numbers could not be reassigned to any other subject. The randomization number was documented in the subject’s clinic notes and in the CRF. The study randomization was stratified by country and was centrally randomized within each country.

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5.4.6.

Assessment of Compliance

Compliance was assessed by the subject’s confirmation on the e-diary that they had administered their daily dose by answering the question: “Was the nasal spray treatment administered?” 5.4.7.

Treatment of Investigational Product Overdose

GSK did not recommend specific treatment to treat a product overdose. In the event of an overdose of study medication, the investigator was to use clinical judgment in treating the overdose and to contact the study medical monitor. It was recommended that the Investigator Brochure for GW685698X [GlaxoSmithKline Document Number RM2004/00130/03] and current VERAMYST prescribing information should be referenced for any safety concerns. 5.4.8.

Nasal Spray Malfunctions

Subjects were instructed to return malfunctioning nasal sprays to the clinic, at which time they were dispensed a new nasal spray. Clinical sites were instructed to return malfunctioning nasal sprays to GSK.

5.5.

Prior and Concomitant Medications and Non-Drug Therapies

5.5.1.

Permitted Medications

All concomitant medications taken during the study were recorded in the eCRF. The minimum requirement was that drug name and the dates of administration be recorded. No other anti-allergy or rhinitis medications, including oral, intranasal, ocular treatments, were permitted during the study. All medications for other disorders could be continued throughout the study, provided the dose remained constant and their use was not expected to affect the subject’s nasal or nonnasal symptoms. Subjects with mild intermittent or very mild asthma could be treated with short-acting inhaled beta2 agonists on an as needed basis only. 5.5.2.

Prohibited Medications

Concomitant use of any prescription or non-prescription medications that could affect the duration /severity of rhinitis, including oral or intranasal treatments, was not permitted during this study. The list below includes specific medications prohibited at any time during the study: •

Intranasal or ocular cromolyn

•

Short-acting prescription or over-the-counter (OTC) antihistamines, including ocular preparations and antihistamines contained in insomnia and ‘nighttime’ pain formulations taken for insomnia

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•

Long-acting antihistamines, including loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, terfenadine

•

Long-acting antihistamine, astemizole, within 12 weeks prior to Visit 1

•

Intranasal antihistamines, including Astelin

•

Corticosteroids: with the exception of topical hydrocortisone (1% or less, or equivalent), subjects had to refrain from use of all corticosteroids during the study

•

Oral or intranasal decongestants

•

Intranasal, oral or inhaled anticholinergics

•

Intranasal medications (other than study treatment)

•

Oral antileukotrienes

•

Long-acting beta-agonists (e.g., salmeterol)

•

Ophthalmic allergy preparations

•

Ocular antihistamines, eyewashes/irrigation solutions, homeopathic preparations, lubricants, sympathomimetic or vasoconstrictor preparations

•

Use of any medications that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole

•

Subcutaneous omalizumab (Xolair)

•

Chronic use of tricyclic antidepressants or other concomitant medications that would affect assessment of the effectiveness of the study medication

•

Immunosuppressive medications (e.g., cyclophosphamide)

•

Nasal Continuous Positive Airway Pressure (C-PAP) device (mask or pillow)

Immunotherapy patients could be enrolled into the study if the immunotherapy was not initiated within 30 days of Visit 1, the dose had remained fixed over the 30 days prior to Visit 1, and the dose remained fixed for the duration of the study. 5.5.3.

Medical Device(s)

No GSK medical devices were involved in this study. GSK provided the In-Check Nasal portable hand-held inspiratory flow meters and face masks (Clement-Clarke International, Harlow, UK) for use in the study. 5.5.4.

Non-drug Therapies

No non-drug therapies were permitted in this study.

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5.6.

Study Assessments and Procedures

5.6.1.

Demographic and Baseline Assessments

The following demographic and baseline information was obtained: age; sex; race; ethnicity, height, weight, duration of the subject’s perennial allergic rhinitis, presence of seasonal allergic rhinitis, and results of skin prick test(s). All subjects also had a physical examination, vital signs assessment, nasal examination, 12-lead ECG, blood hematology and chemistry analyses, and urine pregnancy test (females of childbearing potential). The subjects’ self-rated symptom scores over the 4 days prior to randomization (including the morning of randomization) provided the baseline symptom assessment. All demographic and baseline assessments were completed according to the Time and Events schedule in Table 1. 5.6.2.

Efficacy Assessment

All efficacy measures for nasal (rhinorrhea, nasal congestion, nasal itching, sneezing) symptoms and ocular symptoms (eye itching/ burning, eye tearing/watering, and eye redness) were based on subject-rated, individual symptom assessments as evaluated on a 4-point (0 to 3) categorical scale and recorded on an e-diary. Efficacy measures for the PNIF were based on the subject twice-daily assessments, using an In-Check portable hand-held nasal inspiratory flow meter and face mask, recorded on the e-diary. All efficacy endpoints reflected the change over the entire treatment period. Subjects used the following 0 to 3 scale to assess the severity of each of the symptoms assessed in the study: 0 = none (symptom is not present) 1 = mild (sign/symptom is clearly present but minimal awareness; easily tolerated) 2 = moderate (definite awareness of sign/symptom that is bothersome but tolerable) 3 = severe (sign/symptom is hard to tolerate; causes interference with activities of daily living and/or sleeping) Subjects were instructed to score and document their symptoms in a reflective manner and an instantaneous manner on an electronic diary. •

The reflective rating represented the subject’s symptoms over the preceding 12 hours. This assessment provided information on how effective the treatment was throughout the day and was performed TWICE daily (AM and PM). The AM assessment was performed prior to administering the morning dose and assessed how the subject felt through the night. The PM reflective rating was performed approximately 12 hours after dosing but before bedtime and assessed how the subject felt during the day.

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•

The instantaneous rating represented the subject’s symptoms at the time of the assessment or at that “instant.” The instantaneous rating was performed ONCE daily, in the morning, and was made prior to administering their morning dose. This assessment provided information on the efficacy of the treatment at the end of the 24-hour dosing interval.

5.6.2.1.

•

Primary efficacy endpoint

The primary efficacy endpoint was the mean change from baseline over the entire treatment period in daily, reflective, total nasal symptom scores (rTNSS) The TNSS is equal to the sum of the 4 individual nasal symptom score assessments for rhinorrhea, nasal congestion, nasal itching, and sneezing where each symptom is scored on a scale of 0 to 3. The rTNSS is a rating of the severity of symptoms over the previous 12 hours and was performed in the AM (AM rTNSS) and PM (PM rTNSS). The daily rTNSS is the average of the AM rTNSS and PM rTNSS assessments.

5.6.2.2.

Secondary efficacy endpoints

Two key secondary efficacy endpoints were assessed: •

Mean change from baseline over the entire treatment period in morning (AM), pre-dose, instantaneous total nasal symptom scores (iTNSS) The AM, pre-dose iTNSS is the sum of the 4 individual nasal symptom score assessments for rhinorrhea, nasal congestion, nasal itching, and sneezing performed at the moment immediately prior to taking the daily dose, where each symptom is scored on a scale of 0 to 3.

•

Mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS) The TOSS is equal to the sum of the three individual ocular symptom scores for eye itching/burning, eye tearing/watering, and eye redness, where each symptom is scored on a scale of 0 to 3.

5.6.2.3.

Other secondary efficacy endpoint(s)

Total Nasal Symptoms

•

Mean change from baseline over the entire treatment period in AM rTNSS and PM rTNSS;

•

Mean percent change from baseline over the entire treatment period in daily rTNSS and AM pre-dose iTNSS.

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Individual Nasal Symptoms

•

Mean change from baseline over the entire treatment period in both individual daily reflective nasal symptom scores and AM pre-dose instantaneous nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing;

•

Mean change from baseline over the entire treatment period in both individual AM reflective, and PM reflective, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing.

Total Ocular Symptoms

•

Mean change from baseline over the entire treatment period in AM pre-dose instantaneous, total ocular symptom scores (iTOSS);

•

Mean change from baseline over the entire treatment period in both the AM reflective, total ocular symptom scores (rTOSS) and PM rTOSS;

•

Mean percent change from baseline over the entire treatment period in both the daily rTOSS and the AM, pre-dose iTOSS.

Individual Ocular Symptoms

•

Mean change from baseline over the entire treatment period in both the individual, daily reflective and the AM pre-dose instantaneous, ocular symptom scores for eyes itching/burning, eyes tearing/watering, and eye redness;

•

Mean change from baseline over the entire treatment period in both the individual AM reflective and PM reflective, ocular symptom scores for eyes itching/burning, eyes tearing/watering, and eye redness.

Peak Nasal Inspiratory Flow (PNIF)

•

Mean change from baseline over the entire treatment period in daily PNIF;

•

Mean change from baseline over the entire treatment period in both AM and PM PNIF. The PNIF is an objective measure of nasal airflow obstruction. PNIF measurements were completed and recorded by the subject following assessment of nasal and ocular symptoms in the AM (prior to taking their study medication) and 12 hours later in the PM (after they record their nasal and ocular symptoms on the e-diaries). Three measurements were taken on each occasion and the highest measurement recorded on the e-diary.

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5.6.3.

Onset of Effect Assessment/Maximal Effect

Time to onset of treatment was assessed by the mean change from baseline in AM predose iTNSS and the mean change from baseline in daily rTNSS (Day 1 to Day 28), and supported by the mean change from baseline in AM rTNSS and PM rTNSS. The time to maximal effect was defined as the earliest day that the mean change from baseline in daily rTNSS demonstrated the greatest reduction as compared to placebo (Days 1-28). 5.6.4.

Safety Assessments

Safety was assessed by monitoring of adverse events, vital signs (systolic and diastolic blood pressure and heart rate [pulse]), clinical laboratory tests (hematology and chemistry), and nasal examination. Vital signs (heart rate [pulse], systolic and diastolic blood pressure), physical examinations, and clinical laboratory tests were performed at Visits 1 and 6/Early Withdrawal. Urine pregnancy testing was performed on all females of childbearing potential at Visits 1, 2, 5, and at the last clinic visit (Visit 6 or Early Withdrawal Visit). A nasal examination was performed by the investigator at all visits (Visits 1 to 6 or Early Withdrawal) and the findings recorded on the nasal examination eCRF page. Assessments were done for mucosal bleeding, ulcers, polyps, and fungal infections. The safety endpoints included in the study were: •

Frequency and type of clinical adverse events

•

Clinical laboratory tests (hematology and chemistry)

•

Nasal examinations (mucosal bleeding, ulcers, polyps, and fungal infections)

•

Vital signs (systolic and diastolic blood pressure, heart rate [pulse])

5.6.4.1.

Adverse events

All AEs related to study participation were collected from Visit 1 through Visit 6 or Early Withdrawal. An AE was defined as “Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.” An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

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The definition of AEs included pre- or post-treatment events that occurred as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen). At every visit, after the subject had an opportunity to spontaneously mention any problems, the Investigator inquired about AEs by asking the following standard questions: 1.

“Have you had any (other) medical problems or worsening of any medical problems since your last visit/assessment?”

2.

“Have you taken any new medicines, other than those given to you in this study, since your last visit/assessment?”

Subject e-diary information was reviewed at each visit and if the subject did not mention an event that was recorded, he/she was questioned for further information in order to determine if there was some occurrence of an adverse event. In the event that an AE occurred, the investigator made an assessment of intensity and causality for each AE and SAE reported during the study. The assessment of intensity was based on the investigator’s clinical judgment and was assigned to one of the following categories: •

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

•

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

•

Severe: An event that prevents normal everyday activities.

The assessment of causality (the relationship between investigational product and the occurrence of each AE/SAE) was also based on the investigator’s clinical judgment. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the investigational product was to be considered and investigated. After an initial AE/SAE report, the investigator was to follow each subject and provide further information to GSK on the subject’s condition. All AEs and SAEs documented at a previous visit/contact and designated as ongoing were reviewed at subsequent visits/contacts and followed until resolution, until the condition stabilized, until the event was otherwise explained, or until the subject was lost to follow-up. Once resolved, the appropriate AE/SAE CRF page(s) was updated. The investigator also followed up with any supplemental investigations needed to elucidate the nature and/or causality of the AE or SAE.

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5.6.4.2.

Serious adverse events

All SAEs related to study participation were collected from the time a subject consented to participate in until completion of the study (including any follow-up period). A serious adverse event was defined as any untoward medical occurrence that, at any dose: a

results in death

b

is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe. c

requires hospitalization or prolongation of existing hospitalization

NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. d

results in disability/incapacity

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g.,. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption. e

is a congenital anomaly/birth defect

f

Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

Once an investigator became aware that an SAE had occurred in a study subject, he/she was to report the information to GSK, within 24 hours. The SAE data collection tool was completed as thoroughly as possible with all available details of the event, signed by the investigator (or designee), and forwarded to GSK. If the investigator did not have all information regarding an SAE, he/she did not wait to receive additional information - 3233 -

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before notifying GSK of the event and completing the form. The form was updated when additional information was received. The investigator also provided an assessment of causality at the time of the initial report. 5.6.4.3.

Pregnancies

Any pregnancy that occurred during study participation was reported. Urine pregnancy testing was performed on all females of childbearing potential at Visits 1, 2, 5, and at the last clinic visit (Visit 6 or Early Withdrawal Visit) The investigator, or his/her designee, collected pregnancy information on any female subject who became pregnant while participating in this study. Information concerning the pregnancy was to be recorded on the appropriate form and submitted to GSK within 2 weeks of learning of a subject's pregnancy. The subject was to be followed to determine the outcome of the pregnancy and the status of the mother and child was to be forwarded to GSK. Any premature termination of the pregnancy was also to be reported. A spontaneous abortion is always considered to be a SAE and was to be reported. Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the investigational product, was also reported to GSK. 5.6.4.4.

Clinical laboratory evaluations

Routine laboratory tests (hematology and clinical chemistry) were performed at Visit 1 and Visit 6 or Early Withdrawal visit via a blood sample. Subjects were not required to fast prior to collection of the laboratory specimens. Quest Diagnostics, a central laboratory, analyzed the blood samples and provided a manual to each site containing detailed instructions for collecting all specimens. Printouts from the central laboratory with the results were sent to the site for review by the investigator and were signed and dated by the investigator confirming review. The investigator assessed the results of all clinical laboratory tests to determine each subject’s eligibility to continue in the study, including reviewing liver eligibility criteria (see Section 5.3.2.2). Any subject with all analytes within their respective reference range was eligible to continue. For any subject who had an analyte outside the reference range, the investigator had three options: 1.

Exclude the subject from the study due to the deviant result and/or the uncertain clinical significance of the deviant result.

2.

Repeat, at the earliest opportunity, the test for the analyte on a new specimen to assess the possibility of laboratory error.

3.

Document the subject’s eligibility for the study on the basis of one of the following explanations for the deviant result: •

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•

Normal deviation for age (e.g., elevated alkaline phosphatase).

•

Clinically insignificant deviation from normal values (i.e., in the judgment of the physician/investigator, the deviation did not indicate the presence of a disease state or compromised, predisposing state which renders the subject in question at higher risk than a subject without a similar deviation in laboratory tests).

Abnormal laboratory values resulting in an adverse event or serious adverse event (e.g., hospitalization) were reported to GSK as an adverse event or serious adverse event. Clinically significant abnormal laboratory findings or other abnormal assessments that were detected during the study or were present at baseline and significantly worsened following the start of the study were reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that were associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject’s condition, or that were present or detected at the start of the study and did not worsen, were not reported as AEs or SAEs. The investigator exercised his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment was clinically significant. The analytes shown in Table 3 were evaluated at Visits 1 and 6 (or Early Withdrawal). Table 3

Laboratory Tests

Chemistry Total Bilirubin Alkaline Phosphatase Alanine Aminotransferase (ALT or SGPT) Aspartate Aminotransferase (AST or SGOT) Glucose Creatinine Urea nitrogen Calcium Total Protein Albumin

Hematology Hemoglobin Hematocrit RBC WBC Neutrophils Lymphocytes Monocytes Eosinophils Basophils Platelets

Electrolytes Sodium Potassium

Urine pregnancy tests were done at Visits 1, 2, 5, 6/Early Withdrawal for all female subjects of childbearing potential. RBC = Red blood cell WBC = White blood cell

5.6.4.5.

Physical examination

A physical examination was conducted at Visit 1 (Screening) and Visit 6/Early Withdrawal by the investigator, nurse practitioner, or physician’s assistant listed on the FDA Form 1572. Physical examination results were documented in the source documents only. Any unfavorable changes from the Visit 1 assessment were recorded as an adverse event with the start and stop dates of the event.

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5.6.4.6.

Nasal examination

A nasal examination was performed by the investigator at all visits (Visits 1 to 6 or Early Withdrawal) and the findings recorded on the nasal examination eCRF page. This examination included an evaluation of mucosal bleeding, ulcers, polyps, and fungal infections. Any unfavorable changes not reflective of the symptoms of allergic rhinitis seen at the Visit 1 assessment were recorded as an adverse event with the start and stop dates of the event. Every effort was made to assure the same practitioner performed the nasal examinations for a given subject at all visits for consistency. If symptoms of a nasal fungal infection were present, a fungal culture was performed. A diagnosis of nasal candidiasis was to be reported as an adverse event. 5.6.4.7.

Vital signs

Vital signs (heart rate [pulse], systolic and diastolic blood pressure) were measured at Visit 1 and Visit 6/Early Withdrawal with the subject in the seated position. The subject was seated at least 5 minutes before these measurements were done. A single set of values for heart rate (pulse) and blood pressure (systolic and diastolic) were determined and recorded on the eCRF. The subject's height and weight was also recorded on the eCRF at Visit 1. 5.6.5.

Pharmacogenetic Assessments

Subjects who gave informed consent to participate in the clinical study, met all the criteria required for entry into the study, and had been randomized and received investigational product could take part in the pharmacogenetic (PGx) research. Subjects who consented to participate in the PGx research provided a 10 mL blood sample at Visit 6/Early Withdrawal. These blood samples were stored and may be kept for up to 15 years. Analysis may be conducted at any time there is a potential unexpected or unexplained variation in response to handling fluticasone furoate attributable to genetic variation. 5.6.6.

Health Outcomes Assessments

The Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities RQLQ(S), [Juniper, 1999] is a 28-item, self-administered, disease-specific (allergic rhinitis), quality of life instrument, which assesses quality of life over a one-week interval. Each question is scored from 0 to 6, with higher scores indicating more impairment on quality of life. Items are grouped into seven domains: Activity limitations (3 items), Sleep problems (3 items), Non-nose/eye symptoms (7 items), Practical Problems (3 items), Nasal symptoms (4 items), Eye symptoms (4 items), and Emotional function (4 items). An overall quality of life score can be calculated from the mean score of all items. The minimal important difference (MID) in the RQLQ(S) score that constitutes a clinically relevant improvement in quality of life has been established as -0.50 [Juniper, 1994]. At Visit 2, the randomized subjects completed the first RQLQ(S) prior to randomization. Subjects completed the RQLQ(S) again at Visit 6/Early Withdrawal. - 3536 -

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5.6.6.1.

Questionnaire administration guidelines

To avoid biasing responses, subjects were not told the results of diagnostic tests prior to completing questionnaires. Self-administered questionnaires were completed by the subjects according to the schedule detailed in the Time and Events Schedule (Table 1). Subjects were requested to complete the questionnaires as completely and as accurately as possible. The RQLQ(S) was completed at the beginning of the visit, prior to the medical history and standard adverse event questions (“Have you had any (other) medical problems since your last visit?” and “Have you taken any new medicines (other than those given to you in this study), since your last study visit/assessment?”). The subject was given adequate time to complete all items. If the subject requested help or clarification of any question in the questionnaire, the study personnel instructed the subject to reread the instructions and to give the best answer possible to each question. The study personnel did not provide the subject with an answer to any question. After the subject had completed the questionnaire, the investigator or his designee reviewed the questionnaire for completeness. If the questionnaire (or any portion of it) was incomplete, the subject was given the opportunity to complete any missing items prior to conclusion of the study visit. The investigator was under no obligation to review or to validate the accuracy of the questionnaires. Once the subject returned the questionnaire to the investigator or study personnel, no changes were allowed. If the subject failed to return to the clinic for subsequent study visits, the investigator or his designee contacted the subject and requested that the subject reschedule the visit as soon as possible. If the subject withdrew or was terminated from the study, the investigator requested the subject complete the RQLQ(S) questionnaire at the Early Withdrawal Visit. 5.6.6.2.

Health outcome source documents

Information collected on the eCRF and the health outcome questionnaires were independent components of the study. No attempt was made to reconcile data recorded on the health outcome questionnaires with data recorded in the clinical eCRF, except for the demographic information (e.g., subject number, gender, investigator number, etc.). Upon each subject’s completion of the study, the investigator’s signature on the eCRF signature page signified that each subject had been given the opportunity to complete the health outcome questionnaires as described previously.

5.7.

Data Quality Assurance

This study used Phase Forward’s InForm system. InForm is a web-based clinical trials data management system that provides investigational sites a standardized and validated, remote, electronic data capture system for the collection of clinical trial data. Activities performed using InForm include data entry, modification, review, and validation. Each activity performed carries a unique user identification code and a date-time stamp.

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InForm training for this study was provided to site staff at the Investigator meeting by Clinical Data Management. Additional training was also provided to study monitors at a face-to-face meeting. Site personnel who did not have previous experience with InForm were trained via eLearning modules provided by PharmaLink. The application was fully validated using test data, prior to distributing the url for site use. Encrypted clinical trial data were transmitted from the site via the internet to a firewall-protected network server, and then via an application server into the clinical database (e.g., InForm puts data into a shared drive). An electronic audit trail of all changes made to the eCRF was kept within the InForm system. This audit trail identified the user making the change by userid and by date and time of change. Pre-defined data validation checks were run within the eCRF as data were entered and submitted by authorized site staff. The resulting data queries were then resolved. Additional queries were generated within the eCRF by authorized GSK staff as a result of data review (e.g., source document review, external data reconciliation). Additional QC was carried out by extracting Statistical Analysis Systems (SAS) datasets and comparing printed copies against the eCRF for 6 subjects. The principal investigator electronically signed and dated each InForm casebook attesting to his or her responsibility for the quality of all data included therein and that the data represented a complete and accurate record of each subject’s participation in the study. At the end of the study, once all data queries were resolved, a CD-ROM containing eCRF PDFs (the PDF is a file that contains all of the subject’s eCRF data, the data queries, and a copy of the audit trail) was sent to sites along with a letter explaining how to view the data on the PDF. Upon delivery of the CD-ROM, the study site notified GSK of receipt of the CD. This study used PHT eDiary system, a web-based data entry system that provides for the collection of each subject’s completed data. The application was validated by PHT and User Acceptance performed by authorized GSK staff. Each data entry carries a unique user identification code and a date-time stamp. Subjects entered eDiary data directly into an electronic device called LogPad. Pre-defined, fully validated data validation checks were run within the LogPad as the data were entered and submitted by the subjects. The resulting data queries were resolved by PHT and/or Monitors. This study used a paper RQLQ(S). The data entry application for the RQLQ(S) was designed and validated at Parexel (Sheffield, UK) and RQLQ(S) data were entered using double-dependent data entry at Parexel. Paper validation discrepancies relating to RQLQ(S) data, if not covered by a Standard Clarification Agreement (SCA), were queried using the documented data query process for review and resolution by investigators and if appropriate with reference to the Clinical Study Team members. All the data delivered to GSK by external vendors, (lab, eDiary, RQLQ[S]) were reconciled with the eCRF data and resulting discrepancies were queried within the eCRF. Serious adverse event (SAE) data were documented according to standard GSK practice in the GSK standard InForm eCRF. Upon submission of the SAE entry, a systemgenerated e-mail was sent to the GSK GCSP department to facilitate rapid reporting as outlined in the study protocol. - 3738 -

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Quality control (QC) tasks were conducted in accordance with existing data management standard operating procedures to ensure database accuracy against the data collected in the eCRF, eDiary, and RQLQ(S). QC procedures are in alignment with the International Conference on Harmonization of Good Clinical Practice (ICH GCP). Adverse events and concomitant medications were coded by the autoencoder using a company standard dictionary (GSK Drug dictionary) and an industry standard dictionary (Medical Dictionary for Regulatory Activities [MedDRA]). The eCRF data, the eDiary data, and the paper data (RQLQ[S]) will be archived according to company standard procedures. Subject data was entered into GSK-defined eCRFs transmitted electronically to GSK and combined with data provided from other sources (e.g., diary data, laboratory data) in a validated data system. After data management procedures were completed the database was released on 30 July 2008. Following release the database was frozen on 04 August 2008.

5.8.

Data Analysis Methods

5.8.1.

Timings of Planned Analyses

All planned analyses were performed after sign-off of the Reporting and Analysis Plan (RAP), Attachment 1. After the database was authorized, the study treatments were unblinded and data displays were released. No interim analysis was planned or conducted. 5.8.2.

Sample Size Considerations

The study randomization was planned for equal allocation of subjects among two treatment groups. A total of 288 subjects were required for this study, with 144 subjects in each of the two treatment groups: Fluticasone furoate nasal spray 110 mcg once daily and placebo. The randomization was stratified by country to account for possible country effects on the study outcome due to country-specific medical practices. Data from previous studies of fluticasone furoate suggested that a reasonable assumption for the standard deviation of mean change from baseline over the entire treatment period in daily rTNSS was 2.6. Using a two-sample t-test with a two-sided significance level of 0.05, the proposed sample size should provide 90% power to detect a difference of 1.0 between active treatment and placebo. 5.8.3.

Analysis Populations

The efficacy, safety, and health outcomes analyses used the Intent-to-Treat (ITT) population. The ITT population is defined as all randomized subjects who received at least one dose of study drug.

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Three populations were defined for this study. The primary population was the Intent-to-Treat (ITT) Population. The ITT Population was defined as all subjects who were randomized and received at least one dose of study drug. Unless otherwise specified, analyses based on the ITT Population will include all available data for these subjects. This population was the basis for all summaries, analyses, listings, and figures of demographic, efficacy, safety, and health outcomes data. The All Subjects Screened Population was defined as all subjects who were screened for inclusion in the study. Subject disposition will be summarized for this population. The Screen Failure Population was defined as all subjects screened for inclusion in the study who were discontinued from the study prior to randomization or subjects who were misrandomized and received no administration of study drug. The reasons for withdrawal prior to randomization and serious adverse events during the screening period were to be listed for this population. 5.8.4.

Treatment Comparisons

The primary comparison was made between fluticasone furoate nasal spray110 mcg once daily and placebo nasal spray. The primary efficacy endpoint was the mean change from baseline over the entire treatment period in daily, reflective, total nasal symptom score (daily rTNSS). 5.8.5.

General Considerations for Data Analyses

The diary data comprised the primary data set of interest and Days 1 to 28 (i.e., the average of all on-treatment data during the 4-week treatment period) was the primary time point of interest. In general, discrete variables were summarized using frequency distributions, and continuous variables were summarized using the number of observations, mean, standard deviation or standard error, median, minimum, and maximum. See Attachment 1, Section 8, General Considerations for Data Analyses. 5.8.5.1.

Multicenter studies

The study randomization was stratified by country and was centrally randomized within each country. See Attachment 1, Section 8.1, Multicenter Studies. 5.8.5.2.

Other strata and covariates

In addition to country, baseline value, age, and gender were included as covariates in all efficacy analyses when appropriate. 5.8.5.3.

Examination of subgroups

Subgroup summaries were provided for the primary efficacy endpoint by age group and by country.

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For all adverse events during the treatment period, subgroup summary tables were provided by age group (12 to <18, 18 to <65, and ≥65 years of age), and gender. 5.8.5.4.

Multiple comparison/multiplicity

The primary efficacy endpoint served as a gatekeeper for the interpretation of treatment comparisons for the key secondary efficacy and health outcomes endpoints. If H0 was rejected at the 0.05 level for the primary efficacy endpoint, the conclusion would be there was a difference between fluticasone furoate nasal spray 110 mcg once daily and placebo, and the p-values for the key secondary efficacy and health outcomes endpoints would be interpreted according to the rules for multiplicity adjustment described below. If H0 was not rejected, the conclusion would be there was no difference between fluticasone furoate nasal spray 110 mcg once daily and placebo, and all other p-values would be used for descriptive and exploratory purposes only. To control for multiplicity across the key secondary efficacy endpoints and the health outcomes endpoint (mean change from baseline to endpoint in the global score of the RQLQ[S]), tests of H0 were performed in a sequential manner to control the Type I error rate at 0.05 as follows: 1.

Mean change from baseline over the entire treatment period in AM, pre-dose iTNSS.

2.

Mean change from baseline over the entire treatment period in daily rTOSS.

3.

Mean change from baseline to endpoint in the RQLQ(S) global score.

No multiplicity adjustments were made on the other secondary efficacy endpoints. Any p-values ≤0.05 were identified as nominally significant. 5.8.6.

Data Handling Conventions

For handling of premature withdrawal, missing data, calculations of derived variables, scoring of RQLQ and assessment windows, see Attachment 1, Section 9, Data Handling Conventions. 5.8.7.

Study Population

For summaries of subject disposition, protocol deviations, demographic and baseline characteristics, concomitant medications, and treatment compliance, see Attachment 1, Section 10, Study Population. 5.8.8.

Efficacy Analyses

For analyses of all efficacy measures (i.e., primary, key secondary, and other secondary) see Attachment 1, Section 11, Efficacy Analyses. The primary analysis method was the comparison of treatment groups (fluticasone furoate nasal spray 110 mcg once daily versus placebo) using analysis of covariance (ANCOVA), adjusting for baseline daily rTNSS, country, age, and gender. - 4041 -

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The analysis method used for all secondary nasal and ocular symptom-related endpoints and PNIF was similar to the primary analysis method. The analysis method was based on ANCOVA adjusting for baseline symptom scores, country, age, and gender. 5.8.9.

Safety Analyses

For analyses of safety data, see Attachment 1, Section 12, Safety Analyses. The safety endpoints included in the study were frequency and type of adverse events, results of clinical laboratory tests (hematology and chemistry), results of the nasal examinations, and vital signs (systolic and diastolic blood pressure, heart rate [pulse]). 5.8.10.

Pharmacogenetic Analyses

No analysis of pharmacogenetic samples is currently planned. If at any time a potential unexpected or unexplained variation in drug handling or response is apparent (e.g., pharmacokinetics, efficacy, and/or safety) that may be attributable to genetic variation, then PGx analysis will be considered and will be the topic of a separate report. 5.8.11.

Health Outcomes Analyses

For analyses of RQLQ(S) (health outcomes data) see Attachment 1, Section 13, Health Outcomes Analyses.

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6.

STUDY POPULATION RESULTS

6.1.

Disposition of Subjects

A total of 509 subjects were screened for this study. Of these, 194 subjects were screening failures (Table 6.1). Any subject who was assigned a subject number but not randomized was considered a screening failure. The most common reasons for screening failure were: no diagnosis of PAR and failing to achieve the minimum symptom criteria for randomization. Table 6.2 provides the Listing of Reasons for Exclusion from the Intent-to-Treat population. The ITT population comprised 315 subjects who were randomized and received at least one dose of study medication. The ITT population was used for baseline and disease characteristics summaries and all efficacy, safety, and health outcomes analyses. The number of subjects enrolled at each site ranged between 1 (<1%) and 31 (10%); the number of subjects enrolled in each country ranged from 6 (2%) in Hungary to 114 (36%) in the US (Table 6.3). Table 6.4 provides the Reference Listing of Subject Number to Investigator Number. A total of 96% of subjects completed the study (Table 4). The early withdrawal rate was comparable for both treatment groups. The most common reason for withdrawal was protocol deviation (e.g., failed to meet minimum symptom randomization criteria or exclusion criteria deviation) (Table 6.6 and Table 6.8). The number of subjects completing each treatment visit is shown in Table 6.7. Table 4

Subject Accountability (ITT Population)

Completion Status Completed Not Completed Reason for discontinuation Adverse event Lack of efficacy Protocol deviation Lost to follow-up Withdrew consent

Placebo (N=155)

n (%) subjects FF 110 mcg (N=160)

Total (N=315)

148 (95) 7 (5)

153 (96) 7 (4)

301 (96) 14 (4)

1 (<1) 0 3 (2) 1 (<1) 2 (1)

1 (<1) 0 5 (3) 0 1 (<1)

2 (<1) 0 8 (3) 1 (<1) 3 (<1)

Source: Table 6.5

6.2.

Protocol Deviations

The definition of protocol deviation included failure to meet inclusion or randomization criteria, violation of the exclusion criteria, and use of prohibited medications. The incidence of inclusion/exclusion/randomization criteria deviations and the incidence of

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protocol deviations both were low and similar between the two treatment groups (Table 5). Table 6.9 displays the Listing of Inclusion/Exclusion/Randomization Criteria Deviations and a listing of all protocol deviations is provided in Table 6.11. Table 5

Protocol Deviations (ITT Population)

n (%) subjects Placebo FF 110 mcg (N=155) (N=160) Inclusion/exclusion/randomization criteria deviations Any deviation Inclusion criteria Exclusion criteria Significant concomitant medical conditions Use of corticosteroids Randomization criteria Average of last 8 rTNSS assessments <6 Average of last 8 reflective nasal congestion symptom score assessments <2 Average of last 8 rTOSS assessments <4 Protocol deviations Any deviation Prohibited medications During screening During treatment Other Incorrect dispensing of drug container

3 (2) 0

5 (3) 0

0 1 (<1)

1 (<1) 0

0 1 (<1)

3 (2) 1 (<1)

1 (<1)

2 (1)

5 (3)

3 (2)

2 (1) 4 (3)

2 (1) 2 (1)

1 (<1)

0

Source: Table 6.8, Table 6.10, and Table 6.11

Table 6.12 summarizes the spacing of visits with respect to the visit window specified in the protocol. The number of visits on target was comparable for both treatments over the course of the study (range 91% to 99% and 93% to 98% in the placebo and fluticasone furoate 110 mcg groups, respectively). The treatment blind was not broken for any subject during the study (Table 6.13).

6.3.

Populations Analyzed

The ITT population, used for all efficacy, safety, and health outcomes analyses, was the primary population. The ITT population comprised of 315 subjects (155 in the placebo group and 160 in the fluticasone furoate 110 mcg group).

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6.4.

Demographics and Other Baseline Characteristics

6.4.1.

Demographic Characteristics and Allergy History

Demographic and baseline characteristics were similar between the two treatment groups (Table 6). Table 6

Demographic and Baseline Characteristics (ITT Population)

Age (years) Mean (SD) Range Age group, n (%) 12 to <18 years 18 to <65 years 65 to <75 years ≥75 years Gender, n (%) Female Male Race, n (%) Whitea Blackb Other Ethnicity, n (%) Hispanic/Latino Not Hispanic/Latino Height (cm) Mean (SD) Range Weight (kg) Mean (SD) Range Duration of PAR, n (%) ≥2 to <5 years ≥5 to <10 years ≥10 years

Placebo (N=155)

FF 110 mcg (N=160)

Total (N=315)

39.3 (15.06) 12 – 72

38.1 (14.18) 12 – 80

38.7 (14.61) 12 - 80

9 (6) 141 (91) 5 (3) 0

9 (6) 146 (91) 3 (2) 2 (1)

18 (6) 287 (91) 8 (3) 2 (<1)

110 (71) 45 (29)

103 (64) 57 (36)

213 (68) 102 (32)

140 (90) 11 (7) 4 (3)

149 (93) 3 (2) 8 (5)

289 (92) 14 (4) 12 (4)

2 (1) 153 (99)

6 (4) 154 (96)

8 (3) 307 (97)

168.3 (8.32) 150 – 188

168.7 (9.74) 127 – 188

168.5 (9.06) 127 – 188

75.8 (19.09) 44 – 158

77.3 (19.94) 39 – 145

76.6 (19.51) 39 – 158

19 (12) 31 (20) 105 (68)

30 (19) 33 (21) 97 (61)

49 (16) 64 (20) 202 (64)

Source: Table 6.14 and Table 6.19 a = White is defined as those subjects who chose only the White (Arabic/North African Heritage) and/or White (White/Caucasian/European Heritage) categories; b = Black is defined as those subjects who chose only the African American/African Heritage category

The age of subjects ranged from 12 to 80 years with a mean age of 38.7 years. The majority of subjects were White (90% to 93%). Summaries of race and racial combinations and race and racial combination details are provided in Table 6.15 and

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Table 6.16, respectively. A listing of subject demographic characteristics is provided in Table 6.17. A listing of race is provided in Table 6.18. The majority of subjects had reported having PAR for ≥10 years (61% - 68%). A full summary of the subjects’ allergy history and allergen skin test results is provided in Table 6.19. Concurrent seasonal allergic rhinitis (SAR) was reported by 41% of subjects in each group. Per protocol, subjects with concurrent seasonal allergic rhinitis could participate in the study as long as the seasonal pollen they were allergic to was not present in their geographical area during the study. A listing of allergy history for each subject is provided in Table 6.20. 6.4.2.

Baseline Nasal and Ocular Symptoms

To be randomized at Visit 2, the average of the last eight rTNSS assessments over the four 24-hours periods prior to randomization must have been ≥6 (out of a score of 12), and the average of the last eight reflective symptom assessments for nasal congestion must have been ≥2 (out of a score of 3). For ocular symptoms, at Visit 2 the average of the last eight rTOSS assessments over the four 24-hour periods prior to randomization must have been ≥4 (out of a score of 9). Mean scores over the four 24-hour periods prior to randomization for the total nasal, nasal congestion, and total ocular symptom scores were similar between the two treatment groups (Table 7). All baseline total and individual nasal symptom scores are provided in Table 6.21. Table 6.22 provides baseline total and individual ocular symptom scores.

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Table 7

Baseline TNSS, Nasal Congestion Scores, and TOSS (ITT Population)

TNSSa Daily Reflective AM Instantaneous AM Reflective PM Reflective Nasal Congestionb Daily Reflective AM Instantaneous AM Reflective PM Reflective TOSSc Daily Reflective AM Instantaneous AM Reflective PM Reflective

Placebo (N=155) Mean (SD) 9.1 (1.58) 8.7 (1.98) 9.1 (1.70) 9.1 (1.64)

FF 110 mcg (N=160) Mean (SD) 9.1 (1.77) 8.9 (1.98) 9.1 (1.82) 9.2 (1.83)

2.6 (0.33) 2.6 (0.42) 2.6 (0.37) 2.6 (0.40)

2.6 (0.39) 2.6 (0.43) 2.6 (0.40) 2.5 (0.43)

6.6 (1.38) 6.5 (1.58) 6.5 (1.42) 6.6 (1.45)

6.3 (1.51) 6.3 (1.71) 6.3 (1.57) 6.3 (1.54)

Source: Table 6.21 and Table 6.22 AM = morning; PM = Evening; a = Maximum score for TNSS = 12, b = Maximum score for nasal congestion = 3 c = Maximum score for TOSS = 9

6.4.3.

Other Current Medical Conditions

The incidence of other current medical conditions was similar between the two treatment groups (Table 6.23). The most commonly affected system organ classes were nervous system disorders (28% and 19% in the fluticasone furoate 110 mcg and placebo groups, respectively), musculoskeletal and connective tissue disorders (21% in each group), and respiratory, thoracic and mediastinal disorders (19% and 23% in the fluticasone furoate 110 mcg and placebo groups, respectively). The percentage of subjects with current medical conditions was generally similar for all system organ classes. Electrocardiograms were only assessed at the screening visit. One subject in the placebo group had an abnormal T wave during the screening assessment, which was reported as a pre-treatment adverse event (Table 8.4). The event was considered mild in intensity.

6.5.

Concomitant Medications

Concomitant use of any prescription or OTC medications that might affect the duration/severity of rhinitis was not permitted during the study. The Relationship of Anatomical Therapeutic Classification (ATC) Level 1, Ingredients, and Verbatim Text for concomitant medications taken during the study are provided in Table 6.24.

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6.5.1.

Concomitant Medications Taken During the Screening Period

Concomitant medication use during screening was generally similar between both treatment groups during the screening period (Table 6.25). The most common medications used concurrently during this period for the two treatment groups (placebo, fluticasone furoate 110 mcg) were: ibuprofen (13%, 11%), vitamins (13%, 9%), ethinyloestradiol (10%, 13%), salbutamol (10%, 8%), paracetamol (9%, 6%), and acetylsalicylic acid (5%, 9%). The other medications recorded by the subjects during screening comprised ≤4% incidence of concurrent use (in total across treatment groups). 6.5.2.

Concomitant Medications Taken During the Treatment Period

Concomitant medication use was generally similar between the fluticasone furoate 110 mcg group and the placebo group during the treatment period (65% and 60%, respectively) (Table 6.26). The most common medications used concurrently during this period for the two treatment groups (placebo, fluticasone furoate 110 mcg) were: ibuprofen (14%, 16%), vitamins (13%, 9%), ethinyloestradiol (10%, 13%), paracetamol (11%, 11%), acetylsalicylic acid (8%, 11%), and salbutamol (10%, 8%). The other medications recorded by the subjects during the treatment period comprised ≤4% incidence of concurrent use (in total across treatment groups). A listing of concomitant medications taken during the study period is provided in Table 6.27.

6.6.

Treatment Compliance

To confirm compliance each day during the treatment period, subjects were asked to respond Yes or No to a question on the eDiary that asked if they had administered two sprays into each nostril. Overall, the mean rate of treatment compliance was similar between the two treatment groups (Table 8). The majority of subjects in each treatment group had a compliance rate of ≥90% (77% and 75% in the placebo and fluticasone furoate 110 mcg groups, respectively). Table 8

Treatment Compliance (ITT Population)

Compliance Rate (%) Mean (SD) Range Compliance Category, n (%) ≥90% ≥80% to <90% <80%

Placebo (N=155)

FF 110 mcg (N=160)

Total (N=315)

91.7 (12.75) 7 – 100

93.3 (8.02) 65 – 100

92.5 (10.62) 7 – 100

119 (77) 18 (12) 18 (12)

120 (75) 26 (16) 14 (9)

239 (76) 44 (14) 32 (10)

Source: Table 6.28

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7.

EFFICACY RESULTS

For the primary efficacy endpoint, the key secondary efficacy endpoints, and the global score of RQLQ(S), any p-values for the comparison of fluticasone furoate 110 mcg versus placebo that achieved statistical significance under multiplicity adjustment were identified as inferentially significant for confirmatory purposes (Section 5.8.5.4). For all other efficacy endpoints that corroborate the primary and the key secondary efficacy endpoints, any p-value ≤0.05 for the comparison of fluticasone furoate 110 mcg versus placebo was identified as (nominally) significant without regard to any issues of multiplicity.

7.1.

Primary Efficacy Results

At baseline, the mean daily rTNSS were the same for both treatment groups (Table 9). Mean weekly reductions in daily rTNSS are displayed in Table 9. The LS mean change from baseline over the entire treatment period in daily rTNSS was greater for fluticasone furoate 110 mcg (-3.19) compared with placebo (-2.45). The LS mean difference between the two treatments (-0.741) was inferentially significant (p=0.004) (Table 7.2). Table 9

Daily rTNSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 9.1 (0.13) 155 6.9 (0.20)

FF 110 mcg (N=160) 160 9.1 (0.14) 160 6.1 (0.21)

-1.5 (0.16) -2.3 (0.20) -2.6 (0.22) -2.9 (0.24)

-1.7 (0.15) -2.9 (0.20) -3.6 (0.23) -4.0 (0.24)

-2.2 (0.19) -2.45 (0.24) -

-3.0 (0.19) -3.19 (0.23) -0.741 0.004 -1.24, -0.24

Source: Table 7.1 and Table 7.2 a = entire treatment period; b = based on ANCOVA adjusting for baseline daily rTNSS, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

The treatment difference between fluticasone furoate 110 mcg and placebo was significant for study weeks 2, 3, and 4, but not for Week 1. The LS mean differences ranged from -0.198 (Week 1; p=0.351) to -1.074 (Week 4; p<0.001) (Table 7.2).

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The mean daily rTNSS over the entire treatment period is illustrated in Figure 7.1. A graph of the mean change from baseline in daily rTNSS over the entire treatment period is presented in Figure 2. A placebo response was observed during the entire treatment period. Figure 2

Mean Change from Baseline in Daily rTNSS over the Treatment Period (ITT Population)

Source: Figure 7.2

7.2.

Key Secondary Efficacy Results

7.2.1.

Mean Change from Baseline in AM Pre-dose iTNSS

At baseline, the mean AM pre-dose iTNSS were similar for both treatment groups (Table 10). Mean weekly reductions in AM pre-dose iTNSS are displayed in Table 10. The LS mean change from baseline over the entire treatment period in AM pre-dose iTNSS was greater for fluticasone furoate 110 mcg (-2.97) compared with placebo (-2.29) and LS mean difference between the two treatments (-0.685) was inferentially significant (p=0.010).

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Table 10

AM Pre-dose iTNSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 8.7 (0.16) 155 6.6 (0.22)

FF 110 mcg (N=160) 160 8.9 (0.16) 160 6.0 (0.22)

-1.4 (0.18) -2.1 (0.22) -2.4 (0.24) -2.7 (0.25)

-1.7 (0.16) -2.8 (0.21) -3.4 (0.23) -3.7 (0.25)

-2.1 (0.20) -2.29 (0.25) -

-2.8 (0.19) -2.97 (0.24) -0.685 0.010 -1.20, -0.17

Source: Table 7.3 and Table 7.4 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

The treatment difference between fluticasone furoate 110 mcg and placebo was significant for study weeks 2, 3, and 4, but not for Week 1. The LS mean differences ranged from -0.223 (Week 1; p=0.326) to -0.937 (Week 4; p=0.005) (Table 7.4). A graph of the mean AM pre-dose iTNSS over the entire treatment period is illustrated in Figure 7.3. A graph of the mean change from baseline over the entire treatment period in AM pre-dose iTNSS is presented in Figure 3.

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Figure 3

Mean Change from Baseline in AM Pre-dose iTNSS over the Treatment Period (ITT Population)

Source: Figure 7.4

7.2.2.

Mean Change from Baseline in Daily rTOSS

At baseline, the mean rTOSS was similar for both treatment groups (Table 11). The LS mean change from baseline over the entire treatment period in daily rTOSS was greater for fluticasone furoate 110 mcg (-2.23) compared with placebo (-1.99); however, the LS mean difference between the two treatments (-0.240) was not significant (p=0.243).

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Table 11

Daily rTOSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 6.6 (0.11) 155 4.7 (0.18)

FF 110 mcg (N=160) 160 6.3 (0.12) 160 4.2 (0.16)

-1.3 (0.14) -1.9 (0.17) -2.1 (0.18) -2.4 (0.20)

-1.2 (0.11) -2.0 (0.16) -2.4 (0.18) -2.8 (0.19)

-1.9 (0.16) -1.99 (0.20) -

-2.0 (0.15) -2.23 (0.19) -0.240 0.243 -0.64, 0.16

Source: Table 7.5 and Table 7.6 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

The treatment difference between fluticasone furoate 110 mcg and placebo was not significant for any study week. A graph of the mean daily rTOSS over the entire treatment period is illustrated in Figure 7.5. A graph of the mean change from baseline over the entire treatment period in daily rTOSS is presented in Figure 4.

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Figure 4

Mean Change from Baseline in Daily rTOSS over the Treatment Period (ITT Population)

Source: Figure 7.6

7.3.

Secondary Efficacy Results

7.3.1.

Total Nasal Symptom Scores

7.3.1.1.

Mean change from baseline in AM rTNSS

At baseline, the mean AM rTNSS were the same for both treatment groups (Table 12). The LS mean change from baseline over the entire treatment period in AM rTNSS was greater for fluticasone furoate 110 mcg (-3.15) compared with placebo (-2.40). The LS mean difference between the two treatments (-0.746) was significant (p=0.003).

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Table 12

AM rTNSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 9.1 (0.14) 155 6.9 (0.20)

FF 110 mcg (N=160) 160 9.1 (0.14) 160 6.1 (0.21)

-1.4 (0.17) -2.2 (0.20) -2.6 (0.22) -2.9 (0.24)

-1.7 (0.15) -2.9 (0.21) -3.6 (0.23) -4.0 (0.25)

-2.2 (0.19) -2.40 (0.24) -

-3.0 (0.19) -3.15 (0.23) -0.746 0.003 -1.24, -0.25

Source: Table 7.7 and Table 7.8 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

Graphs of the mean AM rTNSS and the mean change in AM rTNSS over the entire treatment period are presented in Figure 7.7 and Figure 7.8, respectively. 7.3.1.2.

Mean change from baseline in PM rTNSS

At baseline, the mean PM rTNSS were similar for both treatment groups (Table 13). The LS mean change from baseline over the entire treatment period in PM rTNSS was greater for fluticasone furoate 110 mcg (-3.26) compared with placebo (-2.51). The LS mean difference between the two treatments (-0.758) was significant (p=0.004). These results for PM rTNSS were similar to those observed for AM rTNSS (Table 12).

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Table 13

PM rTNSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 9.1 (0.13) 155 6.8 (0.21)

FF 110 mcg (N=160) 160 9.2 (0.14) 160 6.1 (0.21)

-1.5 (0.17) -2.3 (0.21) -2.6 (0.24) -2.9 (0.25)

-1.8 (0.15) -3.0 (0.21) -3.6 (0.23) -4.1 (0.25)

-2.3 (0.20) -2.51 (0.25) -

-3.1 (0.19) -3.26 (0.24) -0.758 0.004 -1.27, -0.25

Source: Table 7.9 and Table 7.10 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

Graphs of the mean PM rTNSS and the mean change from baseline in PM rTNSS over the entire treatment period are presented in Figure 7.9 and Figure 7.10, respectively. 7.3.1.3.

Mean percentage change from baseline in Daily rTNSS

The LS mean percentage change in daily rTNSS over the entire treatment period was greater for the fluticasone furoate 110 mcg group (-35.03%) compared with placebo (-26.39%). The LS mean difference between the two treatments (-8.642%) was significant (p=0.002) (Table 14).

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Table 14

Daily rTNSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) % Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean % Change (SE) LS Mean % Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 9.1 (0.13) 155 6.9 (0.20)

FF 110 mcg (N=160) 160 9.1 (0.14) 160 6.1 (0.21)

-16.2 (1.75) -24.8 (2.18) -28.2 (2.42) -31.3 (2.56)

-18.9 (1.60) -32.3 (2.18) -39.6 (2.42) -43.8 (2.59)

-24.4 (2.05) -26.39 (2.69) -

-33.3 (2.00) -35.03 (2.59) -8.642 0.002 -14.14, -3.15

Source: Table 7.11 and Table 7.12 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean % change in active – LS mean % change in placebo

A graph of the mean percentage change from baseline in daily rTNSS over the entire treatment period is presented in Figure 7.11. 7.3.1.4.

Mean percentage change from baseline in AM Pre-dose iTNSS

The LS mean percentage change in AM pre-dose iTNSS over the entire treatment period was greater for the fluticasone furoate 110 mcg group (-33.52%) compared with placebo (-24.87%). The LS mean difference between the two treatments (-8.645%) was significant (p=0.004) (Table 15).

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Table 15

AM Pre-dose iTNSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) % Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean % Change (SE) LS Mean % Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 8.7 (0.16) 155 6.6 (0.22)

FF 110 mcg (N=160) 160 8.9 (0.16) 160 6.0 (0.22)

-16.0 (1.93) -22.8 (2.36) -27.4 (2.62) -29.8 (2.77)

-19.3 (1.75) -31.5 (2.38) -37.6 (2.56) -41.8 (2.74)

-23.3 (2.21) -24.87 (2.89) -

-32.1 (2.14) -33.52 (2.77) -8.645 0.004 -14.56, -2.73

Source: Table 7.13 and Table 7.14 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean % change in active – LS mean % change in placebo

A graph of the mean percentage change in AM pre-dose iTNSS over the entire treatment period is presented in Figure 7.12. 7.3.2.

Individual Nasal Symptom Scores

7.3.2.1.

Mean change from baseline in daily reflective individual nasal symptom scores

At baseline, mean daily reflective individual nasal symptom scores were the same between the two treatment groups (fluticasone furoate 110 mcg, placebo): rhinorrhea (2.3, 2.3), nasal congestion (2.6, 2.6), nasal itching (2.2, 2.2), and sneezing (2.0, 2.0) (Table 7.15, Table 7.17, Table 7.19, and Table 7.21). The LS mean change from baseline over the entire treatment period for the individual nasal symptom scores was greater for fluticasone furoate 110 mcg (LS mean range: -0.73 to -0.84) compared with placebo (LS mean range: -0.57 to -0.63) (Table 16). The LS mean difference between the two treatments, range from -0.162 (rhinorrhea) to -0.207 (sneezing), was significant (p=0.019 to p=0.003) for all of the individual nasal symptom scores.

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Table 16

Daily Reflective Individual Nasal Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population)

Nasal Symptom Rhinorrhea LS Mean Change (SE) LS Mean Difference p-value 95% CI Nasal Congestion LS Mean Change (SE) LS Mean Difference p-value 95% CI Nasal Itching LS Mean Change (SE) LS Mean Difference p-value 95% CI Sneezing LS Mean Change (SE) LS Mean Difference p-value 95% CI

Placebo (N=155)

FF 110 mcg (N=160)

-0.57 (0.07) -

-0.73 (0.06) -0.162 0.019 -0.30, -0.03

-0.63 (0.06) -

-0.80 (0.06) -0.173 0.009 -0.30, -0.04

-0.63 (0.07) -

-0.82 (0.06) -0.193 0.006 -0.33, -0.06

-0.63 (0.07) -

-0.84 (0.06) -0.207 0.003 -0.34, -0.07

Source: Table 7.16, Table 7.18, Table 7.20, and Table 7.22 SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

7.3.2.2.

Mean change from baseline in AM pre-dose instantaneous individual nasal symptom scores

At baseline, mean AM pre-dose instantaneous individual nasal symptom scores were similar between the two treatment groups (fluticasone furoate 110 mcg, placebo): rhinorrhea (2.3, 2.2), nasal congestion (2.6, 2.6), nasal itching (2.2, 2.2), and sneezing (1.8, 1.7) (Table 7.23, Table 7.25, Table 7.27, and Table 7.29). The LS mean change from baseline over the entire treatment period for the individual nasal symptom scores was greater for fluticasone furoate 110 mcg (LS mean range: -0.68 to -0.81) compared with placebo (LS mean range: -0.51 to -0.66) (Table 17). The LS mean difference between the two treatments, ranging from -0.149 (nasal itching) to 0.194 (nasal congestion), was significant (p=0.046 to p=0.004) for all of the individual nasal symptom scores.

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Table 17

AM Pre-dose Instantaneous Individual Nasal Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population)

Nasal Symptom Rhinorrhea LS Mean Change (SE) LS Mean Difference p-value 95% CI Nasal Congestion LS Mean Change (SE) LS Mean Difference p-value 95% CI Nasal Itching LS Mean Change (SE) LS Mean Difference p-value 95% CI Sneezing LS Mean Change (SE) LS Mean Difference p-value 95% CI

Placebo (N=155)

FF 110 mcg (N=160)

-0.52 (0.07) -

-0.68 (0.07) -0.161 0.033 -0.31, -0.01

-0.51 (0.06) -

-0.71 (0.06) -0.194 0.004 -0.32, -0.06

-0.66 (0.07) -

-0.81 (0.07) -0.149 0.046 -0.30, -0.00

-0.60 (0.07) -

-0.77 (0.07) -0.172 0.018 -0.31, -0.03

Source: Table 7.24, Table 7.26, Table 7.28, and Table 7.30 SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

7.3.2.3.

Mean change from baseline in AM reflective individual nasal symptom scores

At baseline, mean AM reflective individual nasal symptom scores were similar between the two treatment groups (fluticasone furoate 110 mcg, placebo): rhinorrhea (2.3, 2.3), nasal congestion (2.6, 2.6), nasal itching (2.2, 2.2), and sneezing (2.0, 1.9) (Table 7.31, Table 7.33, Table 7.35, and Table 7.37). These tables also provide a summary of individual symptoms and weekly symptom reductions over the entire treatment period. The LS mean change from baseline over the entire treatment period in AM reflective individual nasal symptoms was greater for fluticasone furoate 110 mcg (LS mean range: -0.75 to -0.81) compared with placebo (LS mean range: -0.58 to -0.62) (Table 7.32, Table 7.34, Table 7.36, and Table 7.38). The LS mean difference between the two treatments, ranging from -0.168 (rhinorrhea) to -0.199 (sneezing), was significant (p=0.016 to p=0.004) for all of the individual nasal symptoms.

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7.3.2.4.

Mean change from baseline in PM reflective individual nasal symptom scores

At baseline, mean PM reflective individual nasal symptom scores were similar between the two treatment groups (fluticasone furoate 110 mcg, placebo): rhinorrhea (2.3, 2.3), nasal congestion (2.5, 2.6), nasal itching (2.3, 2.2), and sneezing (2.1, 2.0) (Table 7.39, Table 7.41, Table 7.43, and Table 7.45). These tables also provide a summary of individual symptoms and weekly symptom reductions over the entire treatment period. The LS mean change from baseline over the entire treatment period in PM reflective individual nasal symptoms was greater for fluticasone furoate 110 mcg (LS mean range: -0.73 to -0.87) compared with placebo (LS mean range: -0.57 to -0.66) (Table 7.40, Table 7.42, Table 7.44, and Table 7.46). The LS mean difference between the two treatments, ranging from -0.161 (nasal congestion) to -0.220 (sneezing), was significant (p=0.024 to p=0.002) for all of the individual nasal symptoms. The results of the mean change from baseline for both individual AM and PM rTNSS are similar, with LS mean differences between the two treatment groups being significant for all nasal symptoms. 7.3.3.

Total Ocular Symptom Scores

7.3.3.1.

Mean change from baseline in AM pre-dose iTOSS

At baseline, the mean AM pre-dose iTOSS was similar for both treatment groups (Table 18). The LS mean change from baseline over the entire treatment period in AM pre-dose iTOSS was greater for fluticasone furoate 110 mcg (-1.97) compared with placebo (-1.80). The LS mean difference between the two treatments (-0.173) was not significant (p=0.407).

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Table 18

AM Pre-dose iTOSS (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 6.5 (0.13) 155 4.7 (0.18)

FF 110 mcg (N=160) 160 6.3 (0.14) 160 4.4 (0.17)

-1.3 (0.15) -1.7 (0.18) -2.0 (0.19) -2.2 (0.21)

-1.1 (0.12) -1.8 (0.17) -2.2 (0.18) -2.6 (0.19)

-1.8 (0.17) -1.80 (0.20) -

-1.9 (0.15) -1.97 (0.19) -0.173 0.407 -0.58, 0.24

Source: Table 7.47 and Table 7.48 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

Graphs of the mean AM pre-dose iTOSS and the mean change in AM pre-dose iTOSS over the entire treatment period are presented in Figure 7.13 and Figure 7.14, respectively. 7.3.3.2.

Mean change from baseline in AM rTOSS

At baseline, the mean AM rTOSS was similar for both treatment groups (Table 7.49). The LS mean change from baseline over the entire treatment period in AM rTOSS was greater for fluticasone furoate 110 mcg (-2.19) compared with placebo (-1.92) (Table 7.50). The LS mean difference between the two treatments (-0.271) was not significant (p=0.188). Graphs of the mean AM rTOSS and mean change in AM rTOSS over the entire treatment period are presented in Figure 7.15 and Figure 7.16, respectively. 7.3.3.3.

Mean change from baseline in PM rTOSS

At baseline, the mean PM rTOSS was similar for both treatment groups (Table 7.51). The LS mean change from baseline over the entire treatment period in PM rTOSS was greater for fluticasone furoate 110 mcg (-2.28) compared with placebo (-2.05) (Table 7.52). The LS mean difference between the two treatments (-0.238) was not significant (p=0.260).

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Graphs of the mean PM rTOSS and the mean change from baseline in PM rTOSS over the entire treatment period are presented in Figure 7.17 and Figure 7.18, respectively. 7.3.3.4.

Mean percent change from baseline over the entire treatment period in daily rTOSS

At baseline, the mean daily rTOSS was similar for both treatment groups. The mean percentage change from baseline over the entire treatment period in daily rTOSS was slightly greater for fluticasone furoate 110 mcg (-32.1%) compared with placebo (-29.1%) (Table 7.101). A graph of the mean percentage change from baseline in daily rTOSS is presented in Figure 7.19. 7.3.3.5.

Mean percent change from baseline over the entire treatment period in AM, pre-dose iTOSS

At baseline, the mean AM predose iTOSS was similar for both treatment groups. The mean percentage change from baseline over the entire treatment period in AM predose iTOSS was slightly greater for fluticasone furoate 110 mcg (-29.7%) compared with placebo (-27.1%) (Table 7.102). A graph of the mean percentage change from baseline in AM pre-dose iTOSS is presented in Figure 7.20. 7.3.4.

Individual Ocular Symptom Scores

7.3.4.1.

Mean change from baseline in daily reflective individual ocular symptom scores

At baseline, mean daily reflective individual ocular symptom scores were similar between the two treatment groups (fluticasone furoate 110 mcg, placebo): eye itching/burning (2.2, 2.3), eye tearing/watering (2.1, 2.2), and eye redness (2.0, 2.1) (Table 7.53, Table 7.55, and Table 7.57). The LS mean change from baseline over the entire treatment period in daily reflective individual ocular symptoms was greater for fluticasone furoate 110 mcg (LS mean range: -0.72 to -0.76) compared with placebo (LS mean range: -0.64 to - 0.69) (Table 19). The LS mean difference between the two treatments, range from -0.070 (eye redness) to -0.107 (eye itching/burning), was not significant for any of the individual ocular symptoms.

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Table 19

Daily Reflective Individual Ocular Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population)

Ocular Symptom Eye Itching/Burning LS Mean Change (SE) LS Mean Difference p-value 95% CI Eye Tearing/Watering LS Mean Change (SE) LS Mean Difference p-value 95% CI Eye Redness LS Mean Change (SE) LS Mean Difference p-value 95% CI

Placebo (N=155)

FF 110 mcg (N=160)

-0.64 (0.07) -

-0.75 (0.06) -0.107 0.130 -0.25, 0.03

-0.69 (0.07) -

-0.76 (0.06) -0.072 0.303 -0.21, 0.07

-0.65 (0.07) -

-0.72 (0.07) -0.070 0.341 -0.21, 0.07

Source: Table 7.54, Table 7.56, and Table 7.58 SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

7.3.4.2.

Mean change from baseline in AM pre-dose instantaneous individual ocular symptom scores

At baseline, mean AM pre-dose instantaneous individual ocular symptom scores were similar between the two treatment groups (fluticasone furoate 110 mcg, placebo): eye itching/burning (2.2, 2.3), eye tearing/watering (2.1, 2.1), and eye redness (2.0, 2.0) (Table 7.59, Table 7.61, and Table 7.63). The LS mean change from baseline over the entire treatment period in AM pre-dose instantaneous individual ocular symptoms was greater for fluticasone furoate 110 mcg (LS mean range: -0.63 to -0.67) compared with placebo (LS mean range: -0.58 to - 0.63) (Table 20). The LS mean difference between the two treatments, range from -0.042 (eye redness) to -0.091 (eye itching/burning), was not significant for any of the individual ocular symptoms.

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Table 20

AM Pre-dose Instantaneous Individual Ocular Symptom Scores Over the Entire Treatment Period (Weeks 1-4) (ITT Population)

Ocular Symptom Eye Itching/Burning LS Mean Change (SE) LS Mean Difference p-value 95% CI Eye Tearing/Watering LS Mean Change (SE) LS Mean Difference p-value 95% CI Eye Redness LS Mean Change (SE) LS Mean Difference p-value 95% CI

Placebo (N=155)

FF 110 mcg (N=160)

-0.58 (0.07) -

-0.67 (0.07) -0.091 0.217 -0.24, 0.05

-0.63 (0.07) -

-0.67 (0.07) -0.048 0.515 -0.19, 0.10

-0.59 (0.07) -

-0.63 (0.07) -0.042 0.567 -0.19, 0.10

Source: Table 7.60, Table 7.62, and Table 7.64 SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

7.3.4.3.

Mean change from baseline in AM and PM reflective individual ocular symptom scores

At baseline, mean AM and PM reflective individual ocular symptom scores were similar between the two treatment groups (Table 7.65, Table 7.67, Table 7.69, Table 7.71, Table 7.73, and Table 7.75). The LS mean difference between the two treatments at Weeks 1 to 4 was not significant for any ocular symptoms and the results were similar for AM and PM (Table 7.66, Table 7.68, Table 7.70, Table 7.72, Table 7.74, and Table 7.76). 7.3.5.

Peak Nasal Inspiratory Flow (PNIF)

7.3.5.1.

Mean change from baseline in daily PNIF

At baseline, the mean daily PNIF was similar for both treatment groups (Table 21). The LS mean change from baseline over the entire treatment period in daily PNIF was greater for fluticasone furoate 110 mcg (19.98 L/min) compared with placebo (13.52 L/min). The LS mean difference between the two treatments (6.458 L/min) was significant (p=0.007).

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Table 21

Daily PNIF (L/min; ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 95.0 (3.78) 155 106.5 (3.91)

FF 110 mcg (N=160) 160 96.3 (3.06) 160 114.6 (3.12)

7.1 (1.25) 11.5 (1.75) 13.6 (2.06) 15.5 (2.39)

10.0 (1.23) 18.3 (1.94) 21.5 (2.33) 24.3 (2.52)

11.5 (1.71) 13.52 (2.29) -

18.3 (1.82) 19.98 (2.20) 6.458 0.007 1.77, 11.15

Source: Table 7.77 and Table 7.78 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

7.3.5.2.

Mean change from baseline in AM PNIF

At baseline, the mean AM PNIF was similar for both treatment groups (Table 22). The LS mean change from baseline over the entire treatment period in AM PNIF was greater for fluticasone furoate 110 mcg (19.67 L/min) compared with placebo (13.15 L/min). The LS mean difference between the two treatments (6.520 L/min) was significant (p=0.008).

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Table 22

AM PNIF (L/min; ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 91.8 (3.60) 155 103.1 (3.81)

FF 110 mcg (N=160) 160 93.2 (3.08) 160 111.2 (3.09)

7.4 (1.41) 11.5 (1.86) 12.9 (2.08) 15.0 (2.36)

9.8 (1.36) 18.1 (1.99) 21.6 (2.35) 23.9 (2.53)

11.3 (1.72) 13.15 (2.36) -

18.1 (1.88) 19.67 (2.27) 6.520 0.008 1.69, 11.35

Source: Table 7.79 and Table 7.80 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

7.3.5.3.

Mean change from baseline in PM PNIF

At baseline, the mean PM PNIF was similar for both treatment groups (Table 23). The LS mean change from baseline over the entire treatment period in PM PNIF was greater for fluticasone furoate 110 mcg (20.05 L/min) compared with placebo (13.88 L/min). The LS mean difference between the two treatments (6.175 L/min) was significant (p=0.013).

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Table 23

PM PNIF (L/min; ITT Population)

Baseline (n) Mean (SE) Weeks 1-4a (n) Mean (SE) Change from Baseline, mean (SE) Week 1 Week 2 Week 3 Week 4 Weeks 1-4a Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155) 155 98.5 (4.07) 155 110.1 (4.12)

FF 110 mcg (N=160) 160 99.6 (3.14) 160 117.9 (3.20)

6.8 (1.39) 11.3 (1.89) 14.9 (2.19) 16.0 (2.56)

9.9 (1.33) 18.4 (2.03) 21.5 (2.43) 24.6 (2.61)

11.7 (1.84) 13.88 (2.38) -

18.3 (1.87) 20.05 (2.28) 6.175 0.013 1.31, 11.04

Source: Table 7.81 and Table 7.82 a = entire treatment period; b = based on ANCOVA adjusting for baseline value, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

7.3.6.

Onset of Treatment Effect and Time to Maximum Effect

7.3.6.1.

Onset of treatment effect

The onset of treatment effect was assessed by the mean change from baseline in AM iTNSS (Days 1 to 28), the mean change from baseline in daily rTNSS (Days 1 to 28), and supported by the mean change from baseline in AM rTNSS and PM rTNSS. At baseline, the mean AM pre-dose iTNSS were similar for both treatment groups (8.9 [fluticasone furoate 110 mcg] and 8.7 [placebo]) (Table 7.83). The LS mean change from baseline for AM pre-dose iTNSS was numerically greater for fluticasone furoate 110 mcg compared with placebo beginning on Day 3, but did not reach statistical significance until Day 9 (iTNSS treatment difference: -0.616, p=0.045). The significant treatment difference was then maintained throughout the remainder of the treatment period (p≤0.046), except for Day 10 (p=0.074) and Day 13 (p=0.055) (Table 7.84). A summary of AM pre-dose iTNSS scores on Days 1-28 are presented in Table 7.83. At baseline, the mean daily rTNSS was the same for both treatment groups (9.1 [fluticasone furoate 110 mcg] and 9.1 [placebo]) (Table 7.85). The LS mean difference for the change from baseline ranged from 0.130 (Day 1) to -1.230 (Day 22). A significant treatment difference in LS mean change from baseline for daily rTNSS was first observed on Day 8 (rTNSS treatment difference -0.595; p=0.036). The significant treatment difference was then maintained throughout the remainder of the treatment

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period (p≤0.036), except for Days 10 (p=0.055), 12 (p=0.053), 13 (p=0.146), and 28 (p=0.057) (Table 7.86). At baseline, the mean AM rTNSS was the same for both treatment groups (Table 7.87). The LS mean difference between the two treatments in change from baseline for AM rTNSS for Days 1 to 28 achieved significance at Day 3 (p=0.037) and again on Day 8 (p=0.021) and then sustained significance through Day 27 (p≤0.046), except for Day 12 (p=0.081) (Table 7.88). At baseline, mean PM rTNSS was also similar for both treatment groups (Table 7.89). The LS mean difference between the two treatments in change from baseline for PM rTNSS achieved significance at Day 9 (p=0.031) and was sustained through Day 27 (p≤0.036), except for Days 10, 12, 13, and 16 (Table 7.90). 7.3.6.2.

Time to maximum effect

The time to maximum effect was also evaluated by the mean change from baseline in daily rTNSS for Days 1 to 28. The time to maximal effect was defined as the earliest day during the treatment period that the mean change from baseline in daily rTNSS demonstrated the greatest reduction for the fluticasone furoate 110 mcg treatment compared with placebo. The greatest LS mean difference between the two treatments (maximum effect) occurred on Day 22 (-1.230), p<0.001 (Table 7.86).

7.4.

Subgroup Analyses

7.4.1.

Summary of Primary Endpoint by Age

Mean baseline scores for daily rTNSS were generally similar across treatment groups for all age categories (12 to <18 years, 18 to <65 years, and ≥65 years of age) (Table 24). The mean change from baseline in daily rTNSS over the 4-week treatment period was greater for fluticasone furoate 110 mcg than for placebo in each age group: the 12 to <18 years group (-2.8 [fluticasone furoate 110 mcg], -1.7 [placebo]), the 18 to <65 years group (-3.0 [fluticasone furoate 110 mcg], -2.3 [placebo]), and the ≥65 years group (-3.9 [fluticasone furoate 110 mcg], -1.2 [placebo]). However, the sample sizes for the 12 to <18 years and ≥65 years groups were too small to make meaningful comparisons. In the 18 to <65 years group, the mean change from baseline in daily rTNSS closely resembled the findings for the ITT population since this age group comprised 91% of that population (Table 9).

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Table 24

Change from Baseline in Daily rTNSS by Age Category (ITT Population)

Baseline (n) Mean (SE) Weeks 1-4 (n) Mean Change (SE)

12 to <18 years Placebo FF 110 mcg (N=9) (N=9) 9 9 9.4 (0.53) 9.2 (0.51) 9 9 -1.7 (0.86) -2.8 (0.89)

18 to <65 years Placebo FF 110 mcg (N=141) (N=146) 141 146 9.1 (0.13) 9.1 (0.15) 141 146 -2.3 (0.20) -3.0 (0.20)

≥65 years Placebo FF 110 mcg (N=5) (N=5) 5 5 9.5 (0.83) 9.1 (1.00) 5 5 -1.2 (0.40) -3.9 (0.56)

Source: Table 7.91, Table 7.92, and Table 7.93 SE = Standard error

7.4.2.

Summary of Primary Endpoint by Country

At baseline, the mean daily rTNSS were generally similar across treatment groups for all countries, with the exception of Hungary. The mean change in daily rTNSS in the fluticasone furoate 110 mcg group was numerically greater than for placebo in all countries, although the difference was small for Germany (Table 25). Table 25

Change from Baseline in Daily rTNSS by Country (ITT Population)

Canada Estonia Germany Hungary Russian Federation Slovakia US

Placebo (N=155) 35 9.4 (0.25) -2.1 (0.41) 9 8.9 (0.57) -1.0 (0.89) 30 8.7 (0.24) -2.4 (0.43) 2 7.5 (1.50) -3.6 (0.71) 18 9.7 (0.40) -4.1 (0.66) 5 7.7 (0.35) -1.0 (0.55) 56 9.2 (0.22) -1.9 (0.26)

n Baseline Mean (SE) Mean Change (SE) n Baseline Mean (SE) Mean Change (SE) n Baseline Mean (SE) Mean Change (SE) n Baseline Mean (SE) Mean Change (SE) n Baseline Mean (SE) Mean Change (SE) n Baseline Mean (SE) Mean Change (SE) n Baseline Mean (SE) Mean Change (SE)

Source: Table 7.94, Table 7.95, Table 7.96, Table 7.97, Table 7.98, Table 7.99, and Table 7.100 Note: Mean change is for Weeks 1-4; All subjects had post-baseline observations. SE = Standard error

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FF 110 mcg (N=160) 35 9.1 (0.31) -3.0 (0.38) 8 8.6 (0.58) -2.9 (0.56) 31 8.6 (0.36) -2.7 (0.38) 4 9.4 (0.90) -4.2 (0.73) 18 9.3 (0.37) -4.8 (0.57) 6 8.2 (0.47) -2.9 (1.08) 58 9.6 (0.22) -2.6 (0.33)

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7.5.

Efficacy Conclusions

•

Once-daily fluticasone furoate 110 mcg nasal spray demonstrated inferentially significantly greater improvements (LS mean difference: -0.741, p=0.004) in the nasal symptoms of PAR versus placebo nasal spray in adult and adolescent subjects 12 years of age and older based on the primary endpoint of daily rTNSS (rhinorrhea, nasal congestion, nasal itching, sneezing) over 4 weeks of treatment. In support of the primary endpoint, the LS mean treatment differences for the AM rTNSS and PM rTNSS were also significant for fluticasone furoate 110 mcg (AM, LS mean difference: -0.746, p=0.003; PM, LS mean difference: -0.758, p=0.004).

•

Use of fluticasone furoate 110 mcg nasal spray once daily resulted in an inferentially significant difference between the two treatments in AM pre-dose iTNSS reduction over the treatment period (LS mean difference = -0.685, p=0.010). A significant difference in favor of fluticasone furoate 110 mcg was also seen for all other secondary nasal endpoints.

•

Use of fluticasone furoate 110 mcg nasal spray once daily did not result in a significant difference between the two treatments in daily rTOSS over the treatment period (LS mean difference = -0.240, p=0.243). Fluticasone furoate 110 mcg did not demonstrate significant improvements in any secondary endpoints related to ocular symptoms over the treatment period.

•

Improvements in daily PNIF over the entire treatment period were significantly greater in the fluticasone furoate 110 mcg group compared with the placebo group (LS mean difference = 6.458 L/min, p=0.007).

•

Onset of treatment effect was observed by Day 9 after the first dose based on AM pre-dose iTNSS and Day 8 based on daily rTNSS, and was maintained during the 4week treatment period, except for Days 10 and 13 (AM pre-dose iTNSS) and Days 10, 12, 13, and 28 (daily rTNSS). The greatest LS mean difference between the two treatments in daily rTNSS (maximum effect) occurred on Day 22 (-1.230, p<0.001).

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8.

SAFETY RESULTS

8.1.

Extent of Exposure

The mean number of days of exposure was similar for both treatment groups (28.5 and 28.6 days for the fluticasone furoate 110 mcg and placebo groups, respectively) (Table 26). The majority of subjects (87%) were exposed to at least 28 days of study medication. Two subjects in the fluticasone furoate 110 mcg group and one subject in the placebo group received treatment for 7 days or less. A listing of exposure to study medication by subject number is provided in Table 8.2. Table 26

Extent of Exposure to Study Medication (ITT Population)

No. of subjects, n (%) 1-7 days 8-14 days 15-21 days 22-27 days 28-31 days >31 days Exposure, days Mean (SD) Median Range

Placebo (N=155)

FF 110 mcg (N=160)

Total N=315

1 (<1) 1 (<1) 3 (2) 17 (11) 122 (79) 11 (7)

2 (1) 0 1 (<1) 16 (10) 133 (83) 8 (5)

3 (<1) 1 (<1) 4 (1) 33 (10) 255 (81) 19 (6)

28.6 (3.35) 29.0 6-36

28.5 (3.37) 29.0 4-36

28.6 (3.36) 29.0 4-36

Source: Table 8.1 SD = Standard deviation

8.2.

Adverse Events

Table 8.3 provides the relationship of adverse event, system organ class, preferred term, and verbatim text for the reporting of AEs in this study. A listing of subject numbers for individual AEs is provided in Table 8.9. A listing of all AEs occurring during the study period sorted by treatment group is provided in Table 8.10. A listing of all AEs sorted by preferred AE term is provided in Table 8.11. 8.2.1.

Screening Period

Although subjects had not yet received study treatment during the Screening Period, AEs during this period were assessed according to the treatment group to which they were subsequently randomized. During the screening period, 8 subjects (5%) in the fluticasone furoate 110 mcg group and 10 subjects (6%) in the placebo group reported AEs (Table 8.4). The most common AE reported was headache (fluticasone furoate 110 mcg, 0%; placebo, 2%). None of the other AEs that occurred during the screening period were reported by more than one subject in either treatment group. - 7172 -

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8.2.2.

Treatment Period

Sixty-seven subjects (42%) in the fluticasone furoate 110 mcg group and 52 subjects (34%) in the placebo group experienced at least one AE during the treatment period (Table 27). The most common AE was epistaxis, reported by 15% of subjects in the fluticasone furoate 110 mcg group and 8% of subjects in the placebo group (Table 8.5).

Epistaxis and nasopharyngitis were reported as AEs occurring at a greater than 3% incidence and more common than placebo (Table 27). All reports of nasopharyngitis in both treatment groups were mild or moderate in intensity (Table 8.11). Two subjects (1%) in the fluticasone furoate 110 mcg group and one subject (<1%) in the placebo group reported a nasal ulcer. Two events of nasal polyps were reported for one subject (<1%) in the fluticasone furoate 110 mcg group and one event of nasal polyps was reported for one subject (<1%) in the placebo group. Table 27

AEs Occurring at Greater than or Equal to 1% Incidence and More Common than Placebo (ITT Population)

Subjects with any AE Epistaxis Nasopharyngitis Scaba Arthralgia Cough Pharyngolaryngeal pain Upper respiratory tract infection Bronchitis Nasal ulcer Nausea Respiratory tract infection viral Viral infection Toothache

Placebo (N=155) n (%) 52 (34) 13 (8) 2 (1) 3 (2) 1 (<1) 2 (1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 0 1 (<1) 0

Source: Table 8.6 and Table 8.7 a. System Organ Class = Skin and subcutaneous tissue disorders

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FF 110 mcg (N=160) n (%) 67 (42) 24 (15) 8 (5) 4 (3) 4 (3) 3 (2) 3 (2) 3 (2) 2 (1) 2 (1) 2 (1) 3 (2) 2 (1) 2 (1)

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8.2.3.

Post-Treatment Period

Table 8.8 summarizes AEs that occurred during the post-treatment period (regardless of causal relationship to study medication) by system organ class and preferred term. Two AEs (hyperglycemia in one subject and epistaxis in one subject) occurred in two fluticasone furoate 110 mcg subjects and one AE (hyperbilirubinemia) was reported in a placebo subject during the post-treatment period (see Section 8.7.3). 8.2.4.

Drug-related AEs During the Study Period

A drug-related AE was an event recorded by the investigator as having a reasonable possibility of being caused by the study drug. The number and incidence of drug-related AEs during the treatment and post-treatment periods are shown in Table 28. A listing of the drug-related AEs is presented in Table 8.13. Twenty-four subjects (15%) receiving fluticasone furoate 110 mcg and 11 subjects (7%) receiving placebo experienced AEs deemed to be drug-related by the investigator. Table 28

Drug-related AEs (ITT Population)

Placebo (N=155) n (%) 11 (7) 6 (4) 2 (1) 1 (<1) 1 (<1) 1 (<1) 0 0 0 0 2 (1) 2 (1) 1 (<1)

Subjects with any drug-related AE Epistaxis Nasal dryness Nasal ulcer Nasal discomfort Scaba Sinus headache Increased upper airway secretion Facial pain Pharyngolaryngeal pain Headache Sneezing Nasal septum ulceration

FF 110 mcg (N=160) n (%) 24 (15) 19 (12) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 0 0 0

Source: Table 8.12 a. System Organ Class = Skin and subcutaneous tissue disorders

The most common drug-related AE, epistaxis, was reported by 19 subjects (12%) in the fluticasone furoate 110 mcg group and 6 subjects (4%) in the placebo group. All drugrelated events of epistaxis were mild in intensity and resolved in all subjects except for two subjects in the fluticasone furoate 110 mcg group and one subject in the placebo group. One subject (<1%) in fluticasone furoate 110 mcg group and two subjects (1%) in the placebo group reported drug-related events of nasal septum ulceration or nasal ulcer. All reports were mild in intensity and all occurrences had resolved by end of treatment (Table 8.11). - 7374 -

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Two subjects reported drug-related headaches in the placebo group; there were no drugrelated headaches reported in the fluticasone furoate 110 mcg group. All headaches were moderate in intensity and all had resolved by end of treatment (Table 8.11).

8.3.

Serious Adverse Events

8.3.1.

Deaths

No subjects died during this study. 8.3.2.

Non-Fatal Events

No SAEs were reported during the study (Table 8.14 and Table 8.l5).

8.4.

Adverse Events Leading to Withdrawal from Study

AEs that caused subject withdrawal from treatment are summarized in Table 8.16 and listed by subject in Table 8.17. One subject in the fluticasone furoate 110 mcg group and one subject in the placebo group withdrew from the study because of AEs: • The subject was withdrawn from the study on Day 4 after confirmation of results based on a repeat lab assessment. The event was not resolved at withdrawal and was not considered related to the study treatment. • The event was resolving by end of treatment and was not considered related to the study treatment. These events are discussed in the case narratives (see Section 13).

8.5.

Adverse Events by Age and Gender

Summaries of AEs that occurred during the treatment period are provided by age and gender in Table 8.18 (12 to <18 years), Table 8.19 (18 to <65 years), Table 8.20 (≥65 years), Table 8.21 (females), and Table 8.22 (males). No safety issues were noted in any of these summaries. In the 12 to <18 years age category, one event each of bronchitis and epistaxis were reported in the fluticasone furoate 110 mcg group. No events were reported in the placebo group. The sample size for the 12 to <18 years age category was too small to provide conclusive AE profiling.

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The AE profile of the 18 to <65 years age group was similar to the results from the ITT population described previously since this age group comprised 91% of the ITT population. In the ≥65 years age category, one event of headache was reported in the fluticasone furoate 110 mcg group. In the placebo group, one event each of eye pruritus, ocular hyperemia, and pruritus were reported. The sample size for the ≥65 years category was too small to provide conclusive AE profiling. The incidence and type of AEs seen across treatment groups were generally similar for males and females with no notable differences for any specific type of AE (Table 8.21 and Table 8.22).

8.6.

Pregnancies

One pregnancy was reported in the placebo group during the study; the outcome was unknown at the time of reporting. See the narrative in Section 13 for more information.

8.7.

Clinical Laboratory Evaluations

8.7.1.

Laboratory Values Over Time

Definitions of normal ranges for laboratory values are provided in Table 8.23. Table 8.24 presents a summary of all laboratory values. Table 8.25 presents the summaries of laboratory data outside the normal range for the two treatment groups for each laboratory analyte at Baseline, Week 4, Early Withdrawal, and Endpoint. A summary of laboratory shifts from baseline to endpoint is provided in Table 8.26. 8.7.2.

Individual Subject Changes

8.7.2.1.

Hematology

The number of subjects with shifts to high or to low for hematology analytes between baseline and endpoint (Week 4 or Early Withdrawal) was assessed (Table 29). The hematology laboratory data did not reveal any findings of clinical concern. At endpoint, the majority of subjects in each treatment group (≥87% fluticasone furoate 110 mcg group, ≥93% placebo group) had either no change from baseline in hematology analytes or shifted into the normal range (Table 8.26). The analyte with the most shifts to high or to low was monocytes with 20 subjects in the fluticasone furoate 110 mcg group and 10 subjects in the placebo group. Analytes which did not have any subjects shift to high or to low are not included in Table 29. A listing of those subjects who had at least one abnormal value for any hematology analyte is provided in Table 8.27.

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Table 29

Laboratory Shifts from Baseline to Endpoint – Hematology (ITT Population)

Analyte

Shift

Placebo (N=155) n (%) N=149 5 (3) 2 (1) N=149 6 (4) N=149 10 (7) 1 (<1) N=149 10 (7) N=149 1 (<1) 0 N=149 4 (3) 4 (3) N=149 10 (7) 0 N=149 0 N=147 1 (<1) N=149 5 (3) N=149 3 (2) 1 (<1) N=149 3 (2) 3 (2) N=149 3 (2) 1 (<1) N=149 3 (2) 3 (2) N=149 5 (3) 1 (<1)

Eosinophils to Low to High Eosinophils %

to High

Hematocrit to Low to High Hemoglobin

to Low

Lymphocytes to Low to High Lymphocytes % to Low to High Monocytes to Low to High Monocytes % to High Platelet Count to High Red Blood Cell Count to Low Segmented Neutrophils to Low to High Segmented Neutrophils % to Low to High Total Neutrophils to Low to High Total Neutrophils % to Low to High White Blood Cell Count to Low to High Source: Table 8.26

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FF 110 mcg (N=160) n (%) N=156 5 (3) 3 (2) N=157 5 (3) N=156 7 (4) 2 (1) N=156 8 (5) N=156 1 (<1) 2 (1) N=157 5 (3) 1 (<1) N=156 19 (12) 1 (<1) N=157 1 (<1) N=156 4 (3) N=156 4 (3) N=156 2 (1) 3 (2) N=157 2 (1) 7 (4) N=156 2 (1) 3 (2) N=157 2 (1) 7 (4) N=156 3 (2) 2 (1)

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8.7.2.2.

Clinical chemistry

The number of subjects with shifts to high or to low for clinical chemistry analytes between baseline and endpoint (Week 4 or Early Withdrawal) was assessed (Table 30). The clinical chemistry laboratory data did not reveal any findings of clinical concern. At endpoint, the majority of subjects in each treatment group (≥90% fluticasone furoate 110 mcg group, ≥93% placebo group) had either no change from baseline in clinical chemistry analytes or shifted into the normal range (Table 8.26). No trends were noted for fluticasone furoate 110 mcg versus placebo. The analyte with the most shifts to high or to low was glucose (subjects were not required to be fasting for either Visit 1 or Visit 6 blood draws). Five fluticasone furoate 110 mcg group subjects (3%) had glucose values shift to low and ten subjects (6%) had glucose values shift to high. In the placebo group, six subjects (4%) had glucose values shift to low and four subjects (3%) had glucose values shift to high. Analytes which did not have any subjects shift to high or to low are not included in Table 30. A listing of those subjects who had at least one abnormal value for any clinical chemistry analyte is provided in Table 8.28.

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Table 30

Laboratory Shifts from Baseline to Endpoint – Clinical Chemistry (ITT Population)

Analyte

Shift

Placebo (N=155) n (%) N=150 1 (<1) N=150 2 (1) N=150 2 (1) N=150 4 (3) N=150 0 N=150 1 (<1) N=150 6 (4) 4 (3) N=150 0 N=150 3 (2) N=150 1 (<1) 3 (2)

Alanine Amino Transferase to High Albumin to High Aspartate Amino Transferase to High Calcium to High Creatinine to High Direct Bilirubin to High Glucose to Low to High Sodium to High Total Bilirubin to High Urea to Low to High

FF 110 mcg (N=160) n (%) N=156 3 (2) N=155 3 (2) N=155 2 (1) N=156 1 (<1) N=155 1 (<1) N=155 0 N=156 5 (3) 10 (6) N=156 1 (<1) N=155 2 (1) N=155 2 (1) 2 (1)

Source: Table 8.26

8.7.3.

Abnormalities of Potential Clinical Concern

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Laboratory abnormalities were reported as post-treatment adverse events for one subject in the fluticasone furoate 110 mcg group and one subject in the placebo group (Table 8.8 and Table 8.9). •

The increased glucose was not considered by the investigator to be related to study drug (subjects were not required to be fasting for either Visit 1 or Visit 4 blood draws). •

The AE was reported 6 days later. This adverse event was not considered by the investigator to be related to study drug.

8.8.

Other Safety Evaluations

8.8.1.

Nasal Examination

The investigators performed nasal examinations at all study visits. Assessments were done for mucosal bleeding, ulcers, polyps, and fungal infections. A summary of the nasal examinations is provided in Table 8.29. Four subjects (3%) in the fluticasone furoate 110 mcg group and one subject (<1%) in the placebo group had polyps at Week 4. At Screening, three fluticasone furoate 110 mcg subjects (2%) and one placebo subject (<1%) had polyps. Two subjects (1%) in the fluticasone furoate 110 mcg group and no subjects in the placebo group had ulcers on the turbinates/septum at Week 4. At Screening, two fluticasone furoate 110 mcg subjects (1%) (different subjects than the ones with nasal ulcers at Week 4) and no placebo subjects had ulcers on the turbinates/septum. A listing of subjects with at least one occurrence of worsening ulcers at any time post-baseline is provided in Table 8.31. The incidence of mucosal bleeding increased from 3% to 6% for fluticasone furoate 110 mcg subjects and decreased from 1% to <1% for placebo subjects from randomization to Week 4. A listing of subjects with at least one occurrence of mucosal bleeding at any time post-baseline is provided in Table 8.32. One fluticasone furoate 110 mcg subject and two placebo subjects had clinical evidence of nasal candidiasis during study treatment; all had a negative fungal culture (Table 8.34). A summary of the shifts from the baseline examination to endpoint examination is presented in Table 31. A listing of subjects with at least one abnormal nasal examination result post-baseline is provided in Table 8.33.

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Table 31

Nasal Examination Shifts from Baseline to Endpoint (ITT Population)

Mucosa Bleeding Ulcers Turbinates/Septum Polyposis Turbinates/Septum

Improved No Change Worsened Improved No Change Worsened Improved No Change Worsened

Placebo (N=155) n (%) N=154 3 (2) 149 (97) 2 (1) 0 154 (100) 0 0 154 (100) 0

FF 110 mcg (N=160) n (%) N=160 3 (2) 148 (93) 9 (6) 2 (1) 156 (98) 2 (1) 0 159 (>99) 1 (<1)

Source: Table 8.30

8.8.2.

Vital Signs

Vital signs (systolic blood pressure, diastolic blood pressure, and heart rate) were assessed at baseline and Endpoint. Mean blood pressure results and pulse rates were comparable between groups at baseline and study end (Table 8.35). Systolic blood pressure declined by 3.0 mmHg in the fluticasone furoate 110 mcg group and 2.0 mmHg in the placebo group between Visits 1 and 4. Diastolic blood pressure declined by 2.0 mmHg in the fluticasone furoate 110 mcg group and 0.6 mmHg in the placebo group between Visits 1 and 4. The event was considered moderate in intensity and was resolved at the end of treatment. The investigator did not consider the event to be drug-related. Mean heart rate increased by 1.6 beats per minute (bpm) in the fluticasone furoate 110 mcg group and increased by 0.1 bpm in the placebo group between Visits 1 and 4. A Summary of Change from Baseline in Vital Signs at Endpoint is provided in Table 8.36.

8.9.

Safety Conclusions

•

In this study, fluticasone furoate nasal spray 110 mcg was well-tolerated over 4 weeks of treatment.

•

There were no deaths or non-fatal SAEs during the study.

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•

During the treatment period, the incidence of AEs was 42% in the fluticasone furoate 110 mcg group and 34% in the placebo group. The most common AE was epistaxis, reported by 15% of subjects in the fluticasone furoate 110 mcg group and 8% of subjects in the placebo group. All instances of epistaxis in both treatment groups were mild in intensity.

•

The only AEs reported as occurring at a greater than 3% incidence and more common than placebo were epistaxis and nasopharyngitis (5% and 1% in the fluticasone furoate 110 mcg group and the placebo group, respectively). Two subjects (1%) in the fluticasone furoate 110 mcg group and one subject (<1%) in the placebo group reported a nasal ulcer during the treatment period.

•

The most common drug-related AE was epistaxis, which occurred at incidence rates of 12% in the fluticasone furoate 110 mcg group and 4% in the placebo group.

•

One subject in the fluticasone furoate 110 mcg group withdrew from the study due to a pre-treatment AE of diabetes mellitus. One subject in the placebo group withdrew from the study due to an AE of lower respiratory tract infection. Neither of these events were considered by the investigator to be related to the study treatment.

•

The incidence of laboratory abnormalities was low and similar between the two treatment groups.

•

Findings from the nasal examinations were similar for the two treatment groups, except for an increase in the incidence of mucosal bleeding following 4 weeks treatment with fluticasone furoate 110 mcg compared with placebo.

•

Changes in vital signs were minor and similar across the two treatment groups.

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9.

PHARMACOGENETIC RESULTS

During the course of the study, 239 (76%) subjects provided blood samples for deoxyribonucleic acid (DNA) extraction and pharmacogenetic analysis (PGx). The need to conduct PGx analysis may be identified after a study (or set of studies) of fluticasone furoate has been completed and the study data reviewed. For this reason, samples may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples before then. In special cases, the samples may not be studied. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond to or handle fluticasone furoate.

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10.

HEALTH OUTCOMES RESULTS

Baseline values were slightly lower for subjects assigned fluticasone furoate 110 mcg compared with placebo for the overall RQLQ(S) score and for each of the seven domain scores (Table 32). Comparing the difference of the LS mean change from baseline to endpoint between the two groups, subjects assigned to fluticasone furoate 110 mcg once daily experienced a significant improvement compared with placebo for the overall RQLQ(S) score (LS mean difference: -0.537, p=0.028) and for 4 of the 7 individual domains: Activities (LS mean difference: -0.595, p=0.028), Sleep (LS mean difference: -0.751, p=0.010), Non-Nose/Eye Symptoms (LS mean difference: -0.614, p=0.014), and Nasal Symptoms (LS mean difference:-0.592, p=0.031). A minimally important difference (greater improvement of at least 0.5 over placebo) was observed in favor of fluticasone furoate 110 mcg for the overall RQLQ(S) score as well as for the same 4 individual domains: Activities, Sleep, Non-Nose/Eye Symptoms, and Nasal Symptoms. The difference between treatment groups was not significant for the other 3 individual domains (Practical Problems, Eye Symptoms, and Emotional), although the observed treatment difference for the domain of Practical Problems was -0.569. Table 32

Baseline, Endpoint and LS Mean Change from Baseline to Endpoint for RQLQ(S) Scores (ITT Population)

Overall Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value) Activities Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value) Sleep Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value)

Placebo (N=155)

FF 110 mcg (N=160)

153 3.8 (1.0) 150 2.5 (1.4) 148 -1.22 (0.18) -

156 3.5 (1.1) 158 1.9 (1.4) 154 -1.76 (0.16) -0.537 (p=0.028)

153 3.8 (1.1) 149 2.6 (1.6) 147 -1.18 (0.20) -

150 3.7 (1.3) 155 2.0 (1.5) 147 -1.78 (0.18) -0.595 (p=0.028)

153 3.8 (1.3) 149 2.4 (1.8) 147 -1.24 (0.22) -

150 3.6 (1.6) 156 1.7 (1.6) 147 -1.99 (0.19) -0.751 (p=0.010)

Continued

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Table 32

Baseline, Endpoint and LS Mean Change from Baseline to Endpoint for RQLQ(S) Scores (ITT Population) - Continued

Non-Nose/Eye Symptoms Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value) Practical Problems Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value) Nasal Symptoms Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value) Eye Symptoms Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value) Emotional Baseline (n) Mean (SD) Endpoint (n) Mean (SD) Change from Baseline to Endpoint (n) LS Mean Change (SE) ∆ LS mean (p-value)

Placebo (N=155)

FF 110 mcg (N=160)

151 3.5 (1.3) 149 2.4 (1.5) 145 -0.91 (0.19) -

157 3.1 (1.4) 158 1.7 (1.4) 155 -1.53 (0.16) -0.614 (p=0.014)

151 4.5 (1.2) 150 2.9 (1.8) 146 -1.46 (0.23) -

157 4.2 (1.4) 155 2.3 (1.7) 152 -2.03 (0.19) -0.569 (p=0.058)

154 4.3 (1.0) 150 2.8 (1.5) 149 -1.48 (0.21) -

155 4.1 (1.2) 158 2.2 (1.6) 153 -2.07 (0.18) -0.592 (p=0.031)

155 3.9 (1.2) 150 2.4 (1.6) 150 -1.42 (0.21) -

157 3.5 (1.3) 158 1.9 (1.5) 155 -1.79 (0.18) -0.374 (p=0.174)

151 3.4 (1.4) 149 2.1 (1.7) 147 -1.15 (0.21) -

158 3.2 (1.5) 157 1.6(1.5) 155 -1.63 (0.17) -0.480 (p=0.077)

Source: Table 9.1 and Table 9.2 SD = standard deviation; LS = least square; SE = standard error Note: n for each domain is based on number of responses received.

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11.

DISCUSSION AND CONCLUSIONS

Allergic rhinitis is an IgE-mediated, inflammatory disorder of the upper airway that occurs following allergen exposure. Perennial allergic rhinitis (PAR), which is the focus of this study, is triggered by allergens commonly present in the household environment throughout the year. These include animal dander from household pets, house dust mites, cockroach, and mold spores. Fluticasone furoate, the investigational drug administered in the study, is a novel corticosteroid with potent glucocorticoid activity. In April 2007, fluticasone furoate nasal spray (tradename VERAMYST) was approved by the FDA for the treatment of symptoms of seasonal and perennial allergic rhinitis in adults and children ≥2 years old [VERAMYST Prescribing Information, 2008]. The current PAR study was conducted to determine the efficacy of fluticasone furoate nasal spray 110 mcg for the treatment of both nasal and ocular symptoms associated with PAR in subjects ≥12 years old. Participating subjects had confirmed allergy to appropriate perennial allergen(s) and met pre-defined minimum nasal and ocular symptom criteria for inclusion. Results of this study showed once-daily fluticasone furoate 110 mcg aqueous nasal spray produced greater reductions from baseline in subjects’ self-assessed, allergy nasal symptom scores as compared with placebo nasal spray. These reductions were inferentially significant for the primary endpoint (rTNSS) as well as for the key secondary nasal symptom endpoint (iTNSS). The results of the mean change from baseline for both PM and AM rTNSS were similar, and both support the primary efficacy endpoint of mean change from baseline in daily rTNSS. Mean percent change from baseline for both daily rTNSS and AM pre-dose iTNSS was also significantly greater in the fluticasone furoate nasal spray 110 mcg group compared with the placebo group. Fluticasone furoate treatment resulted in significantly greater improvements in each of the four individual nasal symptoms. A significant difference between the study treatments was not seen for the key secondary ocular symptom endpoint (rTOSS) or for other ocular symptom endpoints, including any of the three individual ocular symptoms (eyes itching/burning, eyes tearing/watering, and eye redness). As an objective measure of nasal airway patency and obstruction, PNIF were also recorded in this study. Improvements in daily PNIF over the 4-week treatment period were significantly greater in the fluticasone furoate 110 mcg group compared with the placebo group. Onset of action was observed on Day 9 based on AM pre-dose iTNSS and on Day 8 based on daily rTNSS and was maintained during the 4-week treatment period, except for Days 10 and 13 (AM pre-dose iTNSS) and Days 10, 12, 13, and 28 (daily rTNSS). Epistaxis was the most common drug-related adverse event with an incidence rate of 12% in the fluticasone furoate nasal spray 110 mcg group and 4% in the placebo group; all instances of epistaxis were mild in intensity. Other drug-related adverse events were rare, with any one event occurring at an incidence of ≤1% of each group. No serious - 8586 -

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adverse events were reported. One subject in the fluticasone furoate nasal spray 110 mcg group was withdrawn due to diabetes mellitus; onset occurred before study treatment was initiated and the event was not considered related to study treatment. One subject in the placebo group was withdrawn due to a lower respiratory tract infection; the event was not considered related to study treatment. One subject in the placebo group became pregnant; at the time of reporting the outcome of the pregnancy was unknown. Subjects assigned to fluticasone furoate nasal spray 110 mcg once daily experienced both significant and clinically meaningful (improvement of at least -0.5 over placebo) improvements compared with placebo in the overall RQLQ(S) score and in 4 of the 7 individual domains: Activities, Sleep, Non-Nose/Eye Symptoms, and Nasal Symptoms. The difference between treatment groups was not significant for three individual domains: Practical Problems, Eye Symptoms, and Emotional.

11.1.

Conclusions

•

Once-daily fluticasone furoate 110 mcg nasal spray demonstrated inferentially significantly greater improvements (LS mean difference: -0.741, p=0.004) in the nasal symptoms of PAR versus placebo nasal spray in adult and adolescent subjects 12 years of age and older based on the primary endpoint of daily rTNSS (rhinorrhea, nasal congestion, nasal itching, sneezing) over 4 weeks of treatment. In support of the primary endpoint, the LS mean treatment differences for the AM rTNSS and PM rTNSS were also significant for fluticasone furoate 110 mcg (AM, LS mean difference: -0.746, p=0.003; PM, LS mean difference: -0.758, p=0.004).

•

Use of fluticasone furoate 110 mcg nasal spray once daily resulted in an inferentially significant difference between the two treatments in AM pre-dose iTNSS reduction over the treatment period (LS mean difference = -0.685, p=0.010). A significant difference in favor of fluticasone furoate 110 mcg was also seen for all other secondary nasal endpoints.

•

Use of fluticasone furoate 110 mcg nasal spray once daily did not result in a significant difference between the two treatments in daily rTOSS over the treatment period (LS mean difference = -0.240, p=0.243). Fluticasone furoate 110 mcg did not demonstrate significant improvements in any secondary endpoints related to ocular symptoms over the treatment period.

•

Improvements in daily PNIF over the entire treatment period were significantly greater in the fluticasone furoate 110 mcg group compared with the placebo group (LS mean difference = 6.458 L/min, p=0.007).

•

Onset of treatment effect was observed by Day 9 after the first dose based on AM pre-dose iTNSS and Day 8 based on daily rTNSS, and was maintained during the 4week treatment period, except for Days 10 and 13 (AM pre-dose iTNSS) and Days 10, 12, 13, and 28 (daily rTNSS). The greatest LS mean difference between the two treatments in daily rTNSS (maximum effect) occurred on Day 22 (-1.230, p<0.001).

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•

Four weeks of treatment with fluticasone furoate 110 mcg resulted in significant improvement in quality of life compared with placebo based on the overall RQLQ(S) score (LS mean difference: -0.537, p=0.028) and for 4 of the 7 individual domains: Activities (LS mean difference: -0.595, p=0.028), Sleep (LS mean difference: -0.751, p=0.010), Non-Nose/Eye Symptoms (LS mean difference: -0.614, p=0.014), and Nasal Symptoms (LS mean difference:-0.592, p=0.031). There also was a minimally important difference (greater improvement of at least 0.5 over placebo) in the fluticasone furoate 110 mcg group for the overall RQLQ(S) score and for these 4 individual domains. The difference between treatment groups was not significant for three individual domains: Practical Problems, Eye Symptoms, and Emotional.

•

During the treatment period, the incidence of AEs was 42% in the fluticasone furoate 110 mcg group and 34% in the placebo group. The only AEs to occur at a greater than 3% incidence and more common than placebo were epistaxis (15% and 8%) and nasopharyngitis (5% and 1%) in the fluticasone furoate 110 mcg group and the placebo group, respectively.

•

No safety issues were identified with findings from vital signs and laboratory values being similar for the two treatment groups.

•

Findings from the nasal examinations were similar for the two treatment groups, except for increase in the incidence of mucosal bleeding following 4 weeks treatment with fluticasone furoate 110 mcg compared with placebo. The incidence of mucosal bleeding increased from 3% to 6% for fluticasone furoate 110 mcg subjects and decreased from 1% to <1% for placebo subjects from randomization to Week 4.

•

The results of this study support the once-daily use of fluticasone furoate 110 mcg nasal spray in adult and adolescent subjects 12 years of age and older for the treatment of symptoms of PAR.

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12.

REFERENCES

Allen A, Down G, Newland A, Reynard K, Rosell V, Salmon E, Scott R. Absolute Bioavailabilty of Intranasal Fluticasone Furoate in Healthy Subjects. Clin Ther 2007;29:1415-1420. Bende M, Carrillo T, Vona, et al. A Randomized Comparison of the Effects of Budesonide and Mometasone Furoate Aqueous Nasal Sprays on Nasal Peak Flow Rate and Symptoms in Perennial Allergic Rhinitis. Ann Allergy Asthma Immunol. 2002; 88:617-623. Bousquet J, van Cauwenberge PB, Khaltaev N, et al. Allergic rhinitis and its impact on asthma: ARIA workshop report. J Allergy Clin Immunol 2001;108(5 Suppl): S153-S161. Committee for Medicinal Products for Human Use (CHMP) Guideline on the Clinical Development of Medicinal Products for the Treatment of Allergic Rhinoconjunctivitis (CHMP/EWP/2455/02); October 2004. Dykewicz MS, Fineman S, Skoner DP, and Workgroup on Rhinitis. Diagnosis and Management of Rhinitis: Complete Guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. Annals of Allergy, Asthma, & Immunology 1998:81(Part II):478-518. Food and Drug Administration (FDA) Guidance for Industry, Draft Guidance for Allergic Rhinitis: Clinical Development Programs for Drug Products, April 2000. http://www.fda.gov/cder/guidance/2718dft.pdf. Accessed August 30, 2005. Foresi A. A comparison of the clinical efficacy and safety of intranasal fluticasone propionate and antihistamines in the treatment of rhinitis. Allergy 2000;62:12-14. GlaxoSmithKline Document Number SH2002/00044/00, The Effects of GW685698X in the Rat Ovalbumin induced Lung Eosinophilia Model, Oxazolone Induced Rat Ear Skin Delayed Type Hypersensitivity Model and the Rat Model of Thymus Involution, 19 August 2002. GlaxoSmithKline Document Number SH2002/00038/00, The Effects of GW685698X in Human NFκΒ, Human API, Human GRE, Human MMTV, Rat TAT, Human Bronchial IL8, Human Estrogen Receptor, Human Progesterone Receptor, Human Mineralocorticoid Receptor, and Human Androgen Receptor Functional Analysis, 12 September 2002. GlaxoSmithKline Document Number RM2004/00130/03. Investigator’s Brochure for Fluticasone Furoate: A Novel Glucocorticoid Receptor Agonist for Intranasal Use in the Treatment of Allergic Rhinitis. 2008. Global Initiative for Asthma (GINA). Guidelines revised 2006. Available at, ginasthma.com; 2006. Accessed July 2, 2007.

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Juniper EF, et al. Determining a Minimal Important Change in a Disease-Specific Quality of Life Questionnaire. J Clin Epidemiol. 1994; 47 (1):81-87. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of the Standardised Version of the Rhinoconjunctivitis Quality of Life Questionnaire. J Allergy Clin Immunol. 1999, 104:364-369. Lemiére C, Bai T, Balter M, et al, on behalf of the Canadian Adult Consensus Group of the Canadian Thoracic Society. Adult Asthma Consensus Guidelines Update 2003. Can Respir J. 2004; 11 (Suppl A):9A-18A. National Asthma Education and Prevention Program (NAEPP) Guidelines for the Diagnosis and Management of Asthma – Expert Panel Report 3, National Institutes of Health, August 28, 2007. Settipane GA. Allergic rhinitis – update. Otolaryngol. Head Neck Surg. 1986;94:470475. Settipane GA, Lieberman P. Update on nonallergic rhinitis. Annals of Allergy, Asthma, & Immunology. 2001;86:494-507. Starling-Schwanz R, Peake HL, Salome CM, et al. Repeatability of Peak Nasal Inspiratory Flow Measurements and Utility for Assessing the Severity of Rhinitis. Allergy. 2005; 60:795-800. VERAMYST® (fluticasone furoate) Prescribing Information. July, 2008. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ. 1998;317:1624-9. Wilson A, Dempsey OJ, Sims EJ. Evaluation of treatment Response in Patients with Seasonal Allergic Rhinitis Using Domiciliary Nasal Peak Inspiratory Flow. Clinical and Experimental Allergy. 2000; 30:833-838. Wilson. 2003 Review, Airflow Obstruction and Peak Nasal Inspiratory Flow (PNIF). Available at www.clement-clarke.com, Accessed September 10, 2007; 2003.

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This section contained patient narratives which are textual descriptions of medical history, treatment and outcome for individual patients who experienced a clinically important adverse event including serious adverse events during the trial. They have been excluded to protect patient privacy. This data may be made available subject to an approved research proposal and a determination of the ability to provide information from the specific narratives whilst protecting the patient’s privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.

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Study Population Data Source Tables Page

Table 6.1 Summary of Screening Subject Disposition (All Subjects Screened Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96

Table 6.2 Listing of Reasons for Screening Failure (Screen Failure Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

Table 6.3 Summary of Subject Enrolment by Investigator (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

116

Table 6.4 Reference Listing of Subject Number to Investigator Number (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118

Table 6.5 Summary of Subject Accountability: End of Study Record (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

130

Table 6.6 Listing of Subject Withdrawals: End of Study Record (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

131

Table 6.7 Summary of Number of Subjects at Each Visit (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

132

Table 6.8 Summary of Inclusion/Exclusion/Randomization Criteria Deviations (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . .

133

Table 6.9 Listing of Inclusion/Exclusion/Randomization Criteria Deviations (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

134

Table 6.10 Summary of Protocol Deviations (Intent-to-Treat Population) . . . .

135

Table 6.11 Listing of Protocol Deviations (Intent-to-Treat Population) . . . . . .

136

Table 6.12 Summary of Visit Spacing Relative to Protocol Specifications (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

137

Table 6.13 Listing of Subjects for Whom the Treatment Blind was Broken During the Study (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .

138

Table 6.14 Summary of Demographic Characteristics (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

139

Table 6.15 Summary of Race and Racial Combinations (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

141

Table 6.16 Summary of Race and Racial Combination Details (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

142

94

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Table 6.17 Listing of Subject Demographic Characteristics (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

143

Table 6.18 Listing of Race (Intent-to-Treat Population) . . . . . . . . . . . . . . . . .

155

Table 6.19 Summary of Allergy History (Intent-to-Treat Population). . . . . . . .

167

Table 6.20 Listing of Allergy History (Intent-to-Treat Population) . . . . . . . . . .

168

Table 6.21 Summary of Baseline Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

197

Table 6.22 Summary of Baseline Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

202

Table 6.23 Summary of Current Medical Conditions (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

206

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

207

Table 6.25 Summary of Concomitant Medications During the Screening Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

231

Table 6.26 Summary of Concomitant Medications During the Treatment Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

240

Table 6.27 Listing of Concomitant Medications During the Study Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

251

Table 6.28 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record (Intent-to-Treat Population) .

432

95

Protocol: FFU111439 Population: All Subjects Screened

Page 1 of 1 Table 6.1 Summary of Screening Subject Disposition

Total (N=509) -----------------------------------------------------------------------------------------------------------Randomized Subjects 315 (62%) Randomized and received at least one dose of study drug (ITT) 315 (62%) (38%) (<1%) (7%) (<1%) (1%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (1%) (14%) (15%)

75 24 14 1 7

(15%) (5%) (3%) (<1%) (1%)

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194 1 35 4 6 1 6 2 4 2 1 1 2 1 1 6 69 75

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96

Screened but not Randomized Appropriate informed consent not obtained No diagnosis of PAR Unwilling to maintain same enviroment through the study Inability to comply with study procedures Illiterate Significant concomitant medical conditions Use of corticosteroids Use of other allergy medications Use of medications that may affect allergic rhinitis or its symptoms Allergy/intolerance Use of contact lenses Use of Nasal Continuous Positive Airway Pressure device Clinical trial/experimental medication experience Current tobacco use Clinically significant laboratory abnormality Average of last 8 rTNSS assessments (last 4 24-hour periods) <6 Average of last 8 reflective nasal symptom score assessments (last 4 24-hour periods) for congestion <2 Average of last 8 rTOSS assessments (last 4 24-hour periods) <4 Completed <80% of assessments on the screening symptom e-diary Study closed/terminated (unspecified) Lost to follow-up Withdrew consent

Protocol: FFU111439 Population: Screen Failure

Page 1 of 19 Table 6.2 Listing of Reasons for Screening Failure

Age Inv. Subject (yr) Sex Ethnicity Reason -----------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

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Page 1 of 2 Table 6.3 Summary of Subject Enrolment by Investigator

Canada

11 (7%) 4 (3%) 5 (3%) 4 (3%) 3 (2%) 3 (2%) 3 (2%) 0 1 (<1%) 1 (<1%) 35 (22%)

19 13 8 7 7 6 4 3 2 1 70

(6%) (4%) (3%) (2%) (2%) (2%) (1%) (<1%) (<1%) (<1%) (22%)

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Total for country

8 (5%) 9 (6%) 3 (2%) 3 (2%) 4 (3%) 3 (2%) 1 (<1%) 3 (2%) 1 (<1%) 0 35 (23%)

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FF 110mcg Country Placebo QD Total Investigator Name (N=155) (N=160) (N=315) ------------------------------------------------------------------------------United States 8 (5%) 9 (6%) 17 (5%) 7 (5%) 8 (5%) 15 (5%) 6 (4%) 6 (4%) 12 (4%) 6 (4%) 5 (3%) 11 (3%) 5 (3%) 5 (3%) 10 (3%) 3 (2%) 7 (4%) 10 (3%) 3 (2%) 6 (4%) 9 (3%) 6 (4%) 2 (1%) 8 (3%) 5 (3%) 2 (1%) 7 (2%) 4 (3%) 2 (1%) 6 (2%) 2 (1%) 3 (2%) 5 (2%) 1 (<1%) 3 (2%) 4 (1%) Total for country 56 (36%) 58 (36%) 114 (36%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 6.3 Summary of Subject Enrolment by Investigator

FF 110mcg Country Placebo QD Total Investigator Name (N=155) (N=160) (N=315) ------------------------------------------------------------------------------Germany 14 (9%) 17 (11%) 31 (10%) 14 (9%) 11 (7%) 25 (8%) 2 (1%) 3 (2%) 5 (2%) Total for country 30 (19%) 31 (19%) 61 (19%) Russian Federation

117

Estonia Total for country Slovakia Total for country Hungary

15 (5%) 11 (3%) 10 (3%) 36 (11%)

7 2 9

(5%) (1%) (6%)

3 5 8

(2%) (3%) (5%)

10 7 17

(3%) (2%) (5%)

5 5

(3%) (3%)

6 6

(4%) (4%)

11 11

(3%) (3%)

1 (<1%) 0 1 (<1%) 2 (1%)

2 2 0 4

(1%) (1%) (3%)

3 (<1%) 2 (<1%) 1 (<1%) 6 (2%)

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Total for country

6 (4%) 7 (4%) 5 (3%) 18 (11%)

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Total for country

9 (6%) 4 (3%) 5 (3%) 18 (12%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 12

Table 6.4 Reference Listing of Subject Number to Investigator Number

Treatment: Placebo Age (yr)

Randomization Date

Treatment start

Treatment stop

Study Center Investigator Subj. Sex status Inv. ID Name Country ----------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.

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Note: When treatment stop date was missing due to subject being lost to follow-up or for any other reason, it is substituted with the study completion/discontinuation date.

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 6.5 Summary of Subject Accountability:

End of Study Record

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) ------------------------------------------------------------------------------------Completion Status Completed 148 (95%) 153 (96%) 301 (96%) Prematurely Withdrawn 7 (5%) 7 (4%) 14 (4%) 1 (<1%) 0 3 (2%) 0 1 (<1%) 2 (1%)

1 (<1%) 0 5 (3%) 0 0 1 (<1%)

2 (<1%) 0 8 (3%) 0 1 (<1%) 3 (<1%)

130

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Primary reason for withdrawal Adverse event Lack of efficacy Protocol deviation Study closed/terminated Lost to follow-up Withdrew consent

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Treatment

Inv.

Page 1 of 1 Table 6.6 Listing of Subject Withdrawals: End of Study Record

Subj.

Treatment Start Date

Date of Discont.

Study Day

Reason for discontinuation

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

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Page 1 of 1 Table 6.7 Summary of Number of Subjects at Each Visit

Visit Description in Placebo FF 110mcg QD Total Weeks (N=155) (N=160) (N=315) ----------------------------------------------------------------------------------Screening 155 (100%) 160 (100%) 315 (100%) Randomization 155 (100%) 160 (100%) 315 (100%) Week 1 153 (99%) 158 (99%) 311 (99%) Week 2 151 (97%) 157 (98%) 308 (98%) Week 3 148 (95%) 153 (96%) 301 (96%) Week 4 148 (95%) 153 (96%) 301 (96%) Early Withdrawal 6 (4%) 7 (4%) 13 (4%)

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Page 1 of 1

Table 6.8 Summary of Inclusion/Exclusion/Randomization Criteria Deviations

FF 110mcg Placebo QD Total Criterion (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------3

Exclusion criteria Exclusion #1: Significant concomitant medical conditions Exclusion #2: Use of corticosteroids

0 1 (<1%)

1 (<1%) 0

1 (<1%) 1 (<1%)

8 rTNSS assessments

0

3

(2%)

3 (<1%)

8 reflective nasal 24-hour periods) for

1 (<1%)

1 (<1%)

2 (<1%)

8 rTOSS assessments

1 (<1%)

2

3 (<1%)

Randomisation criteria Randomisation #1: Average of last (last 4 24-hour periods) <6 Randomisation #2: Average of last symptom score assessments (last 4 congestion <2 Randomisation #3: Average of last (last 4 24-hour periods) <4

(2%)

5

(3%)

(1%)

8

(3%)

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Any Deviation

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Page 1 of 1

Table 6.9 Listing of Inclusion/Exclusion/Randomization Criteria Deviations

Treatment Inv. Subj. Visit Inclusion/Exclusion/Randomization Criteria Deviation ---------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

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Page 1 of 1 Table 6.10 Summary of Protocol Deviations

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) -----------------------------------------------------------------------------------------------------Any Deviation

5

Prohibited Medications During Screening Period ALBUTEROL CLOBETASOL CREAM LOTRICOMB CREME VISINE ORIGINAL

(3%)

8

(3%)

0 1 (<1%) 1 (<1%) 0

1 (<1%) 0 0 1 (<1%)

1 1 1 1

(<1%) (<1%) (<1%) (<1%)

Prohibited Medications During Treatment Period ALBUTEROL CLOBETASOL CREAM LOTRICOMB CREME NYQUIL SEPTOLETE SYMBICORT

0 1 1 1 0 1

1 (<1%) 0 0 0 1 (<1%) 0

1 1 1 1 1 1

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

Other Incorrect dispensing of drug container

1 (<1%)

0

1 (<1%)

(<1%)

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(2%)

(<1%) (<1%) (<1%)

3

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Page 1 of 1 Table 6.11 Listing of Protocol Deviations

Treatment Inv. Subject Protocol deviation ---------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

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Page 1 of 1

Table 6.12 Summary of Visit Spacing Relative to Protocol Specifications

Placebo FF 110mcg QD Visit / Specified Window Actual (N=155) (N=160) -----------------------------------------------------------------------------------Baseline / 7 to 14 days after Early 0 0 Screening visit On Target 151 (97%) 156 (98%) Late 4 (3%) 4 (3%) 0 2 (1%) 0 156 (98%) 2 (1%)

Week 2 / Day 12 - 18

Missed Visit Discontinued Early On Target Late

0 4 (3%) 2 (1%) 148 (95%) 1 (<1%)

0 3 (2%) 0 155 (97%) 2 (1%)

Week 3 / Day 19 - 25

Missed Visit Discontinued Early On Target Late

0 7 (5%) 1 (<1%) 144 (93%) 3 (2%)

0 7 (4%) 0 150 (94%) 3 (2%)

Week 4 / Day 26 - 32

Missed Visit Discontinued Early On Target Late

0 7 (5%) 3 (2%) 141 (91%) 4 (3%)

0 7 (4%) 1 (<1%) 149 (93%) 3 (2%)

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0 2 (1%) 0 153 (99%) 0

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Missed Visit Discontinued Early On Target Late

137

Week 1 / Day 5 - 11

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Page 1 of 1

Table 6.13 Listing of Subjects for Whom the Treatment Blind was Broken During the Study

No data to report

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Page 1 of 2 Table 6.14 Summary of Demographic Characteristics

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------------Age (y) n 155 160 315 Mean 39.3 38.1 38.7 SD 15.06 14.18 14.61 Median 39.0 38.0 38.0 Min. 12 12 12 Max. 72 80 80 n 12 to <18 years 18 to <65 years 65 to <75 years >=75 years

155 9 (6%) 141 (91%) 5 (3%) 0

160 9 (6%) 146 (91%) 3 (2%) 2 (1%)

315 18 (6%) 287 (91%) 8 (3%) 2 (<1%)

Sex

n Female Male

155 110 (71%) 45 (29%)

160 103 (64%) 57 (36%)

315 213 (68%) 102 (32%)

Race (subgroup summaries)[1]

n White Black Other

155 140 (90%) 11 (7%) 4 (3%)

160 149 (93%) 3 (2%) 8 (5%)

315 289 (92%) 14 (4%) 12 (4%)

Ethnicity

n Hispanic or Latino Not Hispanic or Latino

155 2 (1%) 153 (99%)

160 6 (4%) 154 (96%)

315 8 (3%) 307 (97%)

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[1] White = Subjects who chose only the White (Arabic/North African Heritage) and/or White (White/Caucasian/European Heritage) categories on the CRF. Black = Subjects who chose only the African American/African Heritage category on the CRF. Other = All subjects other than White or Black.

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Age Categ.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 6.14 Summary of Demographic Characteristics

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------------Height (cm) n 154 160 314 Mean 168.3 168.7 168.5 SD 8.32 9.74 9.06 Median 168.0 168.0 168.0 Min. 150 127 127 Max. 188 188 188 Weight (kg)

154 75.8 19.09 72.0 44 158

160 77.3 19.94 75.0 39 145

314 76.6 19.51 73.6 39 158

140

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[1] White = Subjects who chose only the White (Arabic/North African Heritage) and/or White (White/Caucasian/European Heritage) categories on the CRF. Black = Subjects who chose only the African American/African Heritage category on the CRF. Other = All subjects other than White or Black.

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n Mean SD Median Min. Max.

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1 Table 6.15 Summary of Race and Racial Combinations

141

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Placebo FF 110mcg QD Total Race (N=155) (N=160) (N=315) -------------------------------------------------------------------------------------------------n 155 160 315 African American/African Heritage 11 (7%) 3 (2%) 14 (4%) American Indian or Alaska Native 0 2 (1%) 2 (<1%) Asian 4 (3%) 3 (2%) 7 (2%) Central/South Asian Heritage 1 (<1%) 3 (2%) 4 (1%) Japanese/East Asian Heritage/ 3 (2%) 0 3 (<1%) South East Asian Heritage Native Hawaiian or other Pacific Islander 0 1 (<1%) 1 (<1%) White 140 (90%) 149 (93%) 289 (92%) African American/African Heritage & Asian & White 0 1 (<1%) 1 (<1%) Asian & White 0 1 (<1%) 1 (<1%)

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Page 1 of 1 Table 6.16 Summary of Race and Racial Combination Details

142

CONFIDENTIAL

Placebo FF 110mcg QD Total Race (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------n 155 160 315 African American/African Heritage 11 (7%) 3 (2%) 14 (4%) American Indian or Alaska Native 0 2 (1%) 2 (<1%) Asian - Central/South Asian Heritage 1 (<1%) 3 (2%) 4 (1%) Asian - East Asian Heritage 0 0 0 Asian - Japanese Heritage 0 0 0 Asian - South East Asian Heritage 3 (2%) 0 3 (<1%) Asian - Mixed Race 0 0 0 Native Hawaiian or other Pacific Islander 0 1 (<1%) 1 (<1%) White - Arabic/North African Heritage 2 (1%) 1 (<1%) 3 (<1%) White - White/Caucasian/European Heritage 138 (89%) 148 (93%) 286 (91%) White - Mixed Race 0 0 0 Mixed Race 0 2 (1%) 2 (<1%)

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 12 Table 6.17 Listing of Subject Demographic Characteristics

Reference Date of Age Height Weight Treatment Inv. Subj. date Birth (yrs) Sex Race Ethnicity (cm) (kg) --------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

143

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 12 Table 6.18 Listing of Race

Treatment Inv. Subj. Race ---------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

155

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1 Table 6.19 Summary of Allergy History

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) ------------------------------------------------------------------------------------------------------Duration of PAR n 155 160 315 >= 2 years to < 5 years 19 (12%) 30 (19%) 49 (16%) >= 5 years to < 10 years 31 (20%) 33 (21%) 64 (20%) >= 10 years 105 (68%) 97 (61%) 202 (64%) SAR

160 94 (59%) 66 (41%)

315 186 (59%) 129 (41%)

n Yes Not Done

155 56 (36%) 99 (64%)

160 62 (39%) 98 (61%)

315 118 (37%) 197 (63%)

Animal Danders

n Yes Not Done

155 92 (59%) 63 (41%)

160 78 (49%) 82 (51%)

315 170 (54%) 145 (46%)

Dust Mites

n Yes Not Done

155 125 (81%) 30 (19%)

160 131 (82%) 29 (18%)

315 256 (81%) 59 (19%)

Cockroaches

n Yes Not Done

155 15 (10%) 140 (90%)

160 10 (6%) 150 (94%)

315 25 (8%) 290 (92%)

n Mean SD Median Min. Max.

155 0.2 0.75 0.0 0 6

160 0.2 0.68 0.0 0 5

315 0.2 0.71 0.0 0 6

Perennial Allergen Test Positive Moulds

167

Diluent control wheal size?

RM2008/00422/00

155 92 (59%) 63 (41%)

CONFIDENTIAL

n No Yes

Protocol: FFU111439 Population: Intent-to-Treat

Treatment

Invid

Subj.

Page 1 of 29 Table 6.20 Listing of Allergy History

Age/ Sex

Screening visit date

PAR Duration (yr)

SAR

Seasonal Allergen Present?

Perennial Allergen Test positive

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

168

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 5 Table 6.21 Summary of Baseline Nasal Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------TNSS Daily Reflective n 155 160 315 Mean (SD) 9.1( 1.58) 9.1( 1.77) 9.1( 1.68) Median 9.0 8.9 9.0 Min - Max 6.0 - 12.0 3.5 - 12.0 3.5 - 12.0 155 8.7( 1.98) 8.8 3.5 - 12.0

160 8.9( 1.98) 9.0 2.0 - 12.0

315 8.8( 1.98) 9.0 2.0 - 12.0

AM Reflective

n Mean (SD) Median Min - Max

155 9.1( 1.70) 9.3 5.3 - 12.0

160 9.1( 1.82) 9.0 3.5 - 12.0

315 9.1( 1.76) 9.0 3.5 - 12.0

PM Reflective

n Mean (SD) Median Min - Max

155 9.1( 1.64) 9.0 5.3 - 12.0

160 9.2( 1.83) 9.0 3.5 - 12.0

315 9.2( 1.73) 9.0 3.5 - 12.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

197

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 5 Table 6.21 Summary of Baseline Nasal Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------Rhinorrhea Daily Reflective n 155 160 315 Mean (SD) 2.3( 0.48) 2.3( 0.53) 2.3( 0.51) Median 2.3 2.3 2.3 Min - Max 0.8 - 3.0 0.0 - 3.0 0.0 - 3.0 155 2.2( 0.61) 2.3 0.0 - 3.0

160 2.3( 0.62) 2.3 0.0 - 3.0

315 2.3( 0.61) 2.3 0.0 - 3.0

AM Reflective

n Mean (SD) Median Min - Max

155 2.3( 0.55) 2.3 0.0 - 3.0

160 2.3( 0.56) 2.3 0.0 - 3.0

315 2.3( 0.55) 2.3 0.0 - 3.0

PM Reflective

n Mean (SD) Median Min - Max

155 2.3( 0.50) 2.3 1.0 - 3.0

160 2.3( 0.55) 2.3 0.0 - 3.0

315 2.3( 0.52) 2.3 0.0 - 3.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

198

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 5 Table 6.21 Summary of Baseline Nasal Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------Nasal Congestion Daily Reflective n 155 160 315 Mean (SD) 2.6( 0.33) 2.6( 0.39) 2.6( 0.36) Median 2.6 2.6 2.6 Min - Max 1.8 - 3.0 1.4 - 3.0 1.4 - 3.0 155 2.6( 0.42) 2.5 1.0 - 3.0

160 2.6( 0.43) 2.7 1.3 - 3.0

315 2.6( 0.42) 2.7 1.0 - 3.0

AM Reflective

n Mean (SD) Median Min - Max

155 2.6( 0.37) 2.8 1.8 - 3.0

160 2.6( 0.40) 2.8 1.5 - 3.0

315 2.6( 0.39) 2.8 1.5 - 3.0

PM Reflective

n Mean (SD) Median Min - Max

155 2.6( 0.40) 2.5 1.5 - 3.0

160 2.5( 0.43) 2.5 1.3 - 3.0

315 2.5( 0.42) 2.5 1.3 - 3.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

199

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 5 Table 6.21 Summary of Baseline Nasal Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------Nasal Itching Daily Reflective n 155 160 315 Mean (SD) 2.2( 0.59) 2.2( 0.54) 2.2( 0.56) Median 2.3 2.1 2.1 Min - Max 0.0 - 3.0 0.4 - 3.0 0.0 - 3.0 155 2.2( 0.65) 2.3 0.0 - 3.0

160 2.2( 0.62) 2.3 0.0 - 3.0

315 2.2( 0.64) 2.3 0.0 - 3.0

AM Reflective

n Mean (SD) Median Min - Max

155 2.2( 0.61) 2.3 0.0 - 3.0

160 2.2( 0.57) 2.3 0.3 - 3.0

315 2.2( 0.59) 2.3 0.0 - 3.0

PM Reflective

n Mean (SD) Median Min - Max

155 2.2( 0.62) 2.3 0.0 - 3.0

160 2.3( 0.56) 2.3 0.5 - 3.0

315 2.2( 0.59) 2.3 0.0 - 3.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

200

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 5 Table 6.21 Summary of Baseline Nasal Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------Sneezing Daily Reflective n 155 160 315 Mean (SD) 2.0( 0.62) 2.0( 0.68) 2.0( 0.65) Median 2.0 2.0 2.0 Min - Max 0.0 - 3.0 0.1 - 3.0 0.0 - 3.0 155 1.7( 0.83) 2.0 0.0 - 3.0

160 1.8( 0.79) 2.0 0.0 - 3.0

315 1.8( 0.81) 2.0 0.0 - 3.0

AM Reflective

n Mean (SD) Median Min - Max

155 1.9( 0.66) 2.0 0.0 - 3.0

160 2.0( 0.70) 2.0 0.0 - 3.0

315 1.9( 0.68) 2.0 0.0 - 3.0

PM Reflective

n Mean (SD) Median Min - Max

155 2.0( 0.63) 2.0 0.0 - 3.0

160 2.1( 0.69) 2.0 0.3 - 3.0

315 2.0( 0.66) 2.0 0.0 - 3.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

201

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 4 Table 6.22 Summary of Baseline Ocular Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------TOSS Daily Reflective n 155 160 315 Mean (SD) 6.6( 1.38) 6.3( 1.51) 6.4( 1.45) Median 6.4 6.1 6.3 Min - Max 3.9 - 9.0 1.0 - 9.0 1.0 - 9.0 155 6.5( 1.58) 6.5 2.0 - 9.0

160 6.3( 1.71) 6.3 1.0 - 9.0

315 6.4( 1.65) 6.3 1.0 - 9.0

AM Reflective

n Mean (SD) Median Min - Max

155 6.5( 1.42) 6.5 3.5 - 9.0

160 6.3( 1.57) 6.0 0.7 - 9.0

315 6.4( 1.50) 6.3 0.7 - 9.0

PM Reflective

n Mean (SD) Median Min - Max

155 6.6( 1.45) 6.5 3.5 - 9.0

160 6.3( 1.54) 6.0 1.0 - 9.0

315 6.5( 1.50) 6.3 1.0 - 9.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

202

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 4 Table 6.22 Summary of Baseline Ocular Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------Eye Itching/Burning Daily Reflective n 155 160 315 Mean (SD) 2.3( 0.47) 2.2( 0.51) 2.3( 0.50) Median 2.3 2.1 2.3 Min - Max 1.0 - 3.0 0.4 - 3.0 0.4 - 3.0 155 2.3( 0.56) 2.3 0.5 - 3.0

160 2.2( 0.60) 2.3 0.0 - 3.0

315 2.2( 0.58) 2.3 0.0 - 3.0

AM Reflective

n Mean (SD) Median Min - Max

155 2.3( 0.50) 2.3 1.0 - 3.0

160 2.2( 0.56) 2.1 0.0 - 3.0

315 2.3( 0.53) 2.3 0.0 - 3.0

PM Reflective

n Mean (SD) Median Min - Max

155 2.3( 0.51) 2.3 1.0 - 3.0

160 2.2( 0.52) 2.1 0.5 - 3.0

315 2.3( 0.52) 2.3 0.5 - 3.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

203

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 4 Table 6.22 Summary of Baseline Ocular Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------Eye Tearing/Watering Daily Reflective n 155 160 315 Mean (SD) 2.2( 0.55) 2.1( 0.59) 2.1( 0.57) Median 2.1 2.0 2.0 Min - Max 0.0 - 3.0 0.0 - 3.0 0.0 - 3.0 155 2.1( 0.64) 2.0 0.3 - 3.0

160 2.1( 0.69) 2.0 0.0 - 3.0

315 2.1( 0.66) 2.0 0.0 - 3.0

AM Reflective

n Mean (SD) Median Min - Max

155 2.2( 0.58) 2.0 0.0 - 3.0

160 2.0( 0.61) 2.0 0.0 - 3.0

315 2.1( 0.60) 2.0 0.0 - 3.0

PM Reflective

n Mean (SD) Median Min - Max

155 2.2( 0.57) 2.0 0.0 - 3.0

160 2.1( 0.62) 2.0 0.0 - 3.0

315 2.1( 0.60) 2.0 0.0 - 3.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

204

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 4 Table 6.22 Summary of Baseline Ocular Symptom Scores

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) --------------------------------------------------------------------------------------------------Eye Redness Daily Reflective n 155 160 315 Mean (SD) 2.1( 0.63) 2.0( 0.63) 2.1( 0.63) Median 2.0 2.0 2.0 Min - Max 0.1 - 3.0 0.0 - 3.0 0.0 - 3.0 155 2.0( 0.70) 2.0 0.0 - 3.0

160 2.0( 0.66) 2.0 0.0 - 3.0

315 2.0( 0.68) 2.0 0.0 - 3.0

AM Reflective

n Mean (SD) Median Min - Max

155 2.1( 0.66) 2.0 0.0 - 3.0

160 2.0( 0.64) 2.0 0.0 - 3.0

315 2.0( 0.65) 2.0 0.0 - 3.0

PM Reflective

n Mean (SD) Median Min - Max

155 2.1( 0.65) 2.0 0.3 - 3.0

160 2.0( 0.65) 2.0 0.0 - 3.0

315 2.1( 0.65) 2.0 0.0 - 3.0

CONFIDENTIAL

n Mean (SD) Median Min - Max

205

AM Instantaneous

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1 Table 6.23 Summary of Current Medical Conditions

Placebo FF 110mcg QD Total System Organ Class (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------------Any Condition 101 (65%) 114 (71%) 215 (68%) 3 (2%) 32 (21%) 1 (<1%)

4 (3%) 33 (21%) 3 (2%)

7 (2%) 65 (21%) 4 (1%)

30 13 5 13 36 21 5 1 20 8 1 6 18 25 24 1 10 9

44 5 4 6 31 23 17 0 12 13 0 5 11 15 27 1 9 8

74 18 9 19 67 44 22 1 32 21 1 11 29 40 51 2 19 17

(19%) (8%) (3%) (8%) (23%) (14%) (3%) (<1%) (13%) (5%) (<1%) (4%) (12%) (16%) (15%) (<1%) (6%) (6%)

(28%) (3%) (3%) (4%) (19%) (14%) (11%) (8%) (8%) (3%) (7%) (9%) (17%) (<1%) (6%) (5%)

(23%) (6%) (3%) (6%) (21%) (14%) (7%) (<1%) (10%) (7%) (<1%) (3%) (9%) (13%) (16%) (<1%) (6%) (5%)

CONFIDENTIAL

206

Blood and lymphatic system disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nervous system disorders Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Vascular disorders Infections and infestations Cardiac disorders General disorders and administration site conditions Injury, poisoning and procedural complications Ear and labyrinth disorders Endocrine disorders Eye disorders Gastrointestinal disorders Hepatobiliary disorders Immune system disorders Metabolism and nutrition disorders

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

207

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM ACETYLSALICYLIC ACID ASS Acetylsalicylic acid+Paracetamol+Caffeine Asaphen Aspirin Aspirin protect Asprin Baby Aspirin (low dose) Kalmopyrin Neuranidal N apirin aspirin baby aspirin bc powder excedrin migraine ALUMINIUM HYDROXIDE GEL, DRIED milanta ASCORBIC ACID Vitamin C vitamin C BALSALAZIDE SODIUM colazol BETAMETHASONE DIPROPIONATE Lotricomb Creme BILE cholenzynum BISMUTH SUBSALICYLATE pepto-bismol BUDESONIDE Rhinocort aqua Symbicort CALCIUM Calcium Calcium + D Calcium with Vitamin D Carbocal calcium calcium plus vitamin D CALCIUM CARBONATE Caltrate Kalmopyrin TUMS Tums Extra strength

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

208

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM CALCIUM D3 (NOS) Calcium D3 CLOTRIMAZOLE Lotricomb Creme DIMETICONE, ACTIVATED milanta DROTAVERINE NoSpa DULCOLAX (NOS) Dulcolax ERGOCALCIFEROL Calcium + D Calcium with Vitamin D calcium plus vitamin D ESOMEPRAZOLE MAGNESIUM Nexium GASTRIC MUCOUS MEMBRANE cholenzynum EXTRACT HYOSCYAMINE SULFATE Levsinex INSULIN ASPART novolog mix 70/30 INSULIN DETEMIR levemir INSULIN LISPRO humalog LACTIC ACID Hylak forte LACTIC-ACID-PRODUCING Hylak forte ORGANISMS LANSOPRAZOLE Prevacid LINUM USITATISSIMUM Flax LOPERAMIDE HYDROCHLORIDE Imodium MAGNESIUM Magnesium MAGNESIUM HYDROXIDE milanta MESALAZINE CANASA Mesalazine Pentasa METFORMIN METFORMIN Metformin METFORMIN HYDROCHLORIDE Merckformin METRONIDAZOLE Metrocream .75 mg Metrogel Metrolotion MINERALS NOS Centrum Vitalux

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

209

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM MUNDISAL (NOS) Mundisal Multiple Ingredient Bilagit Calcium + D Calcium with Vitamin D Centrum GNC Multivitamin Hylak forte Multi Vitamin Multi vitamin Multiple Vitamin Multivitamin Vitalux Women's One-A-Day Multivitamins calcium plus vitamin D cholenzynum milanta miltivitamin multivitamin multivitamn OMEPRAZOLE Losec Omeprazol PRILOSEC Zegerrid omeprazol omeprazole prilosec PANTOPRAZOLE Pantozol Protonix protonix PAPAVERINE HYDROCHLORIDE Bilagit PHENOLPHTHALEIN Bilagit PROBIOTICS (NOS) Probiotics PYRIDOXINE HYDROCHLORIDE Vitamin B6

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

ACYCLOVIR AMOXICILLIN AMOXICILLIN TRIHYDRATE AZITHROMYCIN CEFALEXIN

Acyclovir amoxicillin Augmentin Z-pak Zithromax ApoCephalex Keflex

RM2008/00422/00

ANTIINFECTIVES FOR SYSTEMIC USE

CONFIDENTIAL

210

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM RANITIDINE Ranitidine RANITIDINE HYDROCHLORIDE Zantac zantac RETINOL ACETATE retinoli acetatis oleosa (Vitamin A) SITAGLIPTIN Januvia SODIUM CHLORIDE NASAL SALINE SWEET OIL Sweet Oil TOCOPHEROL Vitamin E vitamin E VITAMIN D NOS Vitamin D VITAMINS NOS Centrum GNC Multivitamin Multi Vitamin Multi vitamin Multiple Vitamin Multivitamin Vitalux Vitamin Women's One-A-Day Multivitamins miltivitamin multivitamin multivitamn ZINC Zinc ZINC GLUCONATE cold-eeze

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

ESTRADIOL ESTROGENS CONJUGATED ESTROGENS ESTERIFIED

Estradiol Oestrogel Prempro Estratest HS 1.25mg-2.5mg Estratest LS Syntest HS Alesse Alesse 28 Bellahexal Cilest Cyclen Birth Control

RM2008/00422/00

ETHINYLOESTRADIOL

CONFIDENTIAL

211

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------ANTIINFECTIVES FOR SYSTEMIC USE CEFUROXIME Xorimax CIPROFLOXACIN Ciprofloxacin CLARITHROMYCIN Biaxin Biaxin XL CLAVULANATE POTASSIUM Augmentin CLINDAMYCIN Sobelin - ingredients: Clindamycin-HCl 1H2O HUMAN PAPILLOMA VIRUS VACCINE HPV Vaccination METHENAMINE Bilagit METRONIDAZOLE Metrocream .75 mg Metrogel Metrolotion MOXIFLOXACIN Avelox Multiple Ingredient Augmentin Cotrim 800 PNEUMOCOCCAL VACCINE Pneuomonica Vaccine SULFAMETHOXAZOLE Cotrim 800 TETANUS TOXOID Tetanus vaccine TRIMETHOPRIM Cotrim 800 Motrim VALACICLOVIR HYDROCHLORIDE valtrex

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

212

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------ANTINEOPLASTIC AND IMMUNOMODULATING ETHINYLOESTRADIOL Desmin 20 AGENTS Desogen Diane 35 Jasmine Lamuna 20 Marvelon Microgynon MinEstrin Minisiston Minulet Necon NovaStep NuvaRing Ortho Evera Tricyclen Valette Yaz ortho Tri Cyclen lo ortho novum 777 ortho-cyclen orthotricyclen seasonique tricylin 28 yasmin IMMUNOTHERAPY{NOS} Immunotherapy Immunotherapy left arm Immunotherapy right arm desensitization (immunotherapy vaccin) immunotherapy MEDROXYPROGESTERONE Medroxyprogesteron MEDROXYPROGESTERONE ACETATE Depo-Clinovir Depo-Provera

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------ANTINEOPLASTIC AND IMMUNOMODULATING MEDROXYPROGESTERONE ACETATE Depoprovera AGENTS Depro Provera Prempro METHOTREXATE Methotrexate ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS

CUCURBITA PEPO

213

BLOOD AND BLOOD FORMING ORGANS

ACETYLSALICYLIC ACID

FERROUS GLUCONATE FERROUS SULPHATE

RM2008/00422/00

AMINO ACIDS NOS CYANOCOBALAMIN

ASS Acetylsalicylic acid+Paracetamol+Caffeine Asaphen Aspirin Aspirin protect Asprin Baby Aspirin (low dose) Kalmopyrin Neuranidal N apirin aspirin baby aspirin bc powder excedrin migraine Hylak forte Vitamin B 12 Vitamin B12 Iron (Ferrous gluconate) ferrous sulfate

CONFIDENTIAL

METRONIDAZOLE

Granu Fink Prosta ingredients: Medical Cucurbita and Saegepalmenfrucht (Sabal) - English unknown Metrocream .75 mg Metrogel Metrolotion

Protocol: FFU111439 Population: Intent-to-Treat

Page 8 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------BLOOD AND BLOOD FORMING ORGANS FOLIC ACID FOLIC ACID Folic Acid folic acid HEPARIN SODIUM Lioton Gel (Heparin) IRON iron PHENPROCOUMON Marcumar SODIUM CHLORIDE NASAL SALINE UREA Gormel Cream CARDIOVASCULAR SYSTEM

214

BETAMETHASONE DIPROPIONATE CANDESARTAN CILEXETIL CARVEDILOL CLONIDINE DILTIAZEM DILTIAZEM HYDROCHLORIDE ENALAPRIL ENALAPRIL MALEATE EZETIMIBE FISH OIL

RM2008/00422/00

FLUOCINOLONE ACETONIDE FUROSEMIDE HEPARIN SODIUM HYDROCHLOROTHIAZIDE

Lotrel ATENOLOL Lipitor Lotensin Lotrel Lotricomb Creme Atacand Atacand plus 16/12.5 Carvedilol Clonidine Diltiazem Cartia enalapril Enabeta Vytorin Fish Oil Fish oil fish oil Synalar furosemide Lioton Gel (Heparin) Accuside Atacand plus 16/12.5 Avalide Dyazide

CONFIDENTIAL

AMLODIPINE BESILATE ATENOLOL ATORVASTATIN CALCIUM BENAZEPRIL HYDROCHLORIDE

Protocol: FFU111439 Population: Intent-to-Treat

Page 9 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

215

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM HYDROCHLOROTHIAZIDE Hydrochlorothiazid hydrochlorothiazide INDAPAMIDE Arifon IRBESARTAN Avalide Avapro LIDOCAINE Lidocain 1% LISINOPRIL Lisinopril lisinopril METOPROLOL Metoprolol metoprolol METOPROLOL SUCCINATE Betaloc Zok METOPROLOL TARTRATE Betaloc Metohexal MONASCUS PURPUREUS red yeast rice MOXONIDINE Moxobeta Multiple Ingredient Accuside Atacand plus 16/12.5 Avalide Dyazide Lotrel Vytorin NICOTINIC ACID Niacin OLMESARTAN Benicar OMEGA-3 MARINE TRIGLYCERIDES Omega 3 omega 3 PERINDOPRIL coversyl QUINAPRIL Accuside RAMIPRIL Ramipril ROSUVASTATIN CALCIUM Crestor SIMVASTATIN Simvastatin Simvol Vytorin simvastatin TELMISARTAN Micardis 40

Protocol: FFU111439 Population: Intent-to-Treat

Page 10 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM TRANDOLAPRIL Mavik TRIAMTERENE Dyazide VALSARTAN Diovan VERAPAMIL Verapamil DERMATOLOGICALS

CLINDAMYCIN

216

CLOBETASOL PROPIONATE CLOTRIMAZOLE DIPHENHYDRAMINE DIPHENHYDRAMINE CITRATE DIPHENHYDRAMINE HYDROCHLORIDE FLUOCINOLONE ACETONIDE LACTIC ACID LEVOMENTHOL LIDOCAINE LINOLEIC ACID METRONIDAZOLE

THYMOL

RM2008/00422/00

MOMETASONE FUROATE Multiple Ingredient

Acyclovir Skinoren Benadryl Septolete Lotricomb Creme Rhinocort aqua Symbicort Sobelin - ingredients: Clindamycin-HCl 1H2O Clobetasol cream Lotricomb Creme Excedrin PM diphenhydramine Advil PM Simply Sleep Synalar Hylak forte Bilagit Septolete Lidocain 1% Omega 369 Metrocream .75 mg Metrogel Metrolotion Nasonex Bellahexal Diane 35 Lotricomb Creme Septolete

CONFIDENTIAL

ACYCLOVIR AZELAIC ACID BENADRYL (NOS) BENZALKONIUM CHLORIDE BETAMETHASONE DIPROPIONATE BUDESONIDE

Protocol: FFU111439 Population: Intent-to-Treat

Page 11 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------DERMATOLOGICALS TOCOPHEROL Vitamin E vitamin E UREA Gormel Cream GENITO URINARY SYSTEM AND SEX HORMONES ACETIC ACID CLINDAMYCIN CLOTRIMAZOLE CUCURBITA PEPO

217

DESOGESTREL

DIENOGEST DROSPIRENONE ESTRADIOL

ETHINYLOESTRADIOL

RM2008/00422/00

ESTROGENS CONJUGATED ESTROGENS ESTERIFIED

CONFIDENTIAL

CYPROTERONE ACETATE

Apple Cider Vinegar Sobelin - ingredients: Clindamycin-HCl 1H2O Lotricomb Creme Granu Fink Prosta ingredients: Medical Cucurbita and Saegepalmenfrucht (Sabal) - English unknown Androcur Bellahexal Diane 35 Cerazette Desmin 20 Desogen Lamuna 20 Marvelon Valette Jasmine Yaz yasmin Estradiol Oestrogel Prempro Estratest HS 1.25mg-2.5mg Estratest LS Syntest HS Alesse Alesse 28 Bellahexal Cilest

Protocol: FFU111439 Population: Intent-to-Treat

Page 12 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

218

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------GENITO URINARY SYSTEM AND SEX HORMONES ETHINYLOESTRADIOL Cyclen Birth Control Desmin 20 Desogen Diane 35 Jasmine Lamuna 20 Marvelon Microgynon MinEstrin Minisiston Minulet Necon NovaStep NuvaRing Ortho Evera Tricyclen Valette Yaz ortho Tri Cyclen lo ortho novum 777 ortho-cyclen orthotricyclen seasonique tricylin 28 yasmin ETONOGESTREL NuvaRing GESTODENE Minulet HORMONE REPLACEMENT THERAPY hormone replacent therapy (NOS) IBUPROFEN Advil Advil Liqui Gel Advil Liqui gel Advil PM IBUPROFEN

Protocol: FFU111439 Population: Intent-to-Treat

Page 13 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

219

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------GENITO URINARY SYSTEM AND SEX HORMONES IBUPROFEN Ibuprofen Ibuprophen Nurofen advil ibubeta ibuprofen LACTIC ACID Hylak forte LEVONORGESTREL Alesse Alesse 28 Microgynon Minisiston NovaStep seasonique MAGNESIUM HYDROXIDE milanta MEDROXYPROGESTERONE Medroxyprogesteron MEDROXYPROGESTERONE ACETATE Depo-Clinovir Depo-Provera Depoprovera Depro Provera Prempro METHYLTESTOSTERONE Estratest HS 1.25mg-2.5mg Estratest LS Syntest HS METRONIDAZOLE Metrocream .75 mg Metrogel Metrolotion Multiple Ingredient Alesse Alesse 28 Bellahexal Cilest Cyclen Birth Control Desmin 20 Desogen Diane 35

Protocol: FFU111439 Population: Intent-to-Treat

Page 14 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

220

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------GENITO URINARY SYSTEM AND SEX HORMONES Multiple Ingredient Estratest HS 1.25mg-2.5mg Estratest LS Granu Fink Prosta ingredients: Medical Cucurbita and Saegepalmenfrucht (Sabal) - English unknown Jasmine Lamuna 20 Marvelon Microgynon MinEstrin Minisiston Minulet Necon NovaStep NuvaRing Ortho Evera Prempro Syntest HS Tricyclen Valette Yaz ortho Tri Cyclen lo ortho novum 777 ortho-cyclen orthotricyclen seasonique tricylin 28 yasmin NAPROXEN Naproxen naproxen NAPROXEN SODIUM Aleve aleve NORELGESTROMIN Ortho Evera

Protocol: FFU111439 Population: Intent-to-Treat

Page 15 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

MUSCULO-SKELETAL SYSTEM

ACETYLSALICYLIC ACID

RM2008/00422/00

ASS Acetylsalicylic acid+Paracetamol+Caffeine Asaphen Aspirin Aspirin protect Asprin Baby Aspirin (low dose) Kalmopyrin Neuranidal N apirin aspirin baby aspirin bc powder excedrin migraine

CONFIDENTIAL

221

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------GENITO URINARY SYSTEM AND SEX HORMONES NORETHISTERONE Camila Necon ortho novum 777 NORETHISTERONE ACETATE MinEstrin NORGESTIMATE Cilest Cyclen Birth Control Tricyclen ortho Tri Cyclen lo ortho-cyclen orthotricyclen tricylin 28 PAPAVERINE HYDROCHLORIDE Bilagit PROGESTERONE Prometrium SERENOA REPENS Granu Fink Prosta ingredients: Medical Cucurbita and Saegepalmenfrucht (Sabal) - English unknown VACCINIUM MACROCARPON cranberry tablets

Protocol: FFU111439 Population: Intent-to-Treat

Page 16 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

222

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------MUSCULO-SKELETAL SYSTEM ALENDRONATE SODIUM Fosamax ALLOPURINOL Milurit allopurinol CARISOPRODOL Carisoprodol CELECOXIB Celebrex COLCHICINE colchizin DICLOFENAC Diclofenac GLUCOSAMINE Glucosamine glucosamine IBUPROFEN Advil Advil Liqui Gel Advil Liqui gel Advil PM IBUPROFEN Ibuprofen Ibuprophen Nurofen advil ibubeta ibuprofen LEVOMENTHOL Bilagit Septolete MEFENAMIC ACID Apo-Mefenamic MELOXICAM Apo-Meloxicam Movalis NAPROXEN Naproxen naproxen NAPROXEN SODIUM Aleve aleve RISEDRONATE SODIUM Actonel SODIUM IBANDRONATE boniva SULINDAC Sulindac TETRAZEPAM Tetrazepam

Protocol: FFU111439 Population: Intent-to-Treat

Page 17 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

223

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------NERVOUS SYSTEM ACETYLSALICYLIC ACID ASS Acetylsalicylic acid+Paracetamol+Caffeine Asaphen Aspirin Aspirin protect Asprin Baby Aspirin (low dose) Kalmopyrin Neuranidal N apirin aspirin baby aspirin bc powder excedrin migraine ALPRAZOLAM Xanax BUPROPION bupropion BUPROPION HYDROCHLORIDE Wellbutrin welburtin xl CAFFEINE Acetylsalicylic acid+Paracetamol+Caffeine Coffeinum Neuranidal N Ratio-Lenoltec acetamenophen/ caffiene bc powder excedrin migraine CITALOPRAM Cipralex citalopram CITALOPRAM HYDROBROMIDE Celexa celexa CITRAMON (NOS) Citramon CLONIDINE Clonidine CODEINE Ratio-Lenoltec

Protocol: FFU111439 Population: Intent-to-Treat

Page 18 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

224

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------NERVOUS SYSTEM DEXTROPROPOXYPHENE NAPSILATE Darvocet-N 50 darvocet DIAZEPAM Diazepam DOXYLAMINE SUCCINATE NyQuil Nyquil DULOXETINE HYDROCHLORIDE Cymbalta ESCITALOPRAM OXALATE Lexapro ESZOPICLONE Lunesta FLUOXETINE HYDROCHLORIDE Prozac GABAPENTIN Gabapentin HYDROCODONE hydrocodone/ acetamenophen IBUPROFEN Advil Advil Liqui Gel Advil Liqui gel Advil PM IBUPROFEN Ibuprofen Ibuprophen Nurofen advil ibubeta ibuprofen LIDOCAINE Lidocain 1% LORAZEPAM lorazepam MEFENAMIC ACID Apo-Mefenamic MIRTAZAPINE remeron Multiple Ingredient Acetylsalicylic acid+Paracetamol+Caffeine Advil PM Darvocet-N 50 Excedrin PM Kalmopyrin Neuranidal N Norco

Protocol: FFU111439 Population: Intent-to-Treat

Page 19 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

225

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------NERVOUS SYSTEM Multiple Ingredient Ratio-Lenoltec Tramacet acetamenophen/ caffiene bc powder darvocet excedrin migraine hydrocodone/ acetamenophen OXYCODONE oxycodone PARACETAMOL Acetaminophen Acetaminphen Acetylsalicylic acid+Paracetamol+Caffeine Darvocet-N 50 Excedrin PM Extra Strength Tylenol Neuranidal N Norco NyQuil Nyquil Paracetamol Ratio-Lenoltec Tramacet Tylenol Tylenol Extra Strength Tylenol Extra-strength Tylenol extra-strenght acetamenophen acetamenophen/ caffiene acetaminophen darvocet excedrin migraine hydrocodone/ acetamenophen tylenol tylenol arthritis

Protocol: FFU111439 Population: Intent-to-Treat

Page 20 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CHOLEINIC SODIUM

Bilagit

DRY PANCREAS

cholenzynum

RESPIRATORY SYSTEM

ACETYLCYSTEINE AMBAZONE AMBROXOL HYDROCHLORIDE BENADRYL (NOS) BENZALKONIUM CHLORIDE BETAMETHASONE DIPROPIONATE BUDESONIDE

Acetylcystein Faringosept Halixol Benadryl Septolete Lotricomb Creme Rhinocort aqua Symbicort Zyrtec chlorpheniramine Ratio-Lenoltec NyQuil

CETIRIZINE HYDROCHLORIDE CHLORPHENAMINE CODEINE DEXTROMETHORPHAN HYDROBROMIDE

RM2008/00422/00

Pharmacological properties cannot be referenced

CONFIDENTIAL

226

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------NERVOUS SYSTEM PARACETAMOL tylenol extra strength PAROXETINE HYDROCHLORIDE Paroxetin Paxil PREGABALIN Lyrika Pregabalin QUETIAPINE FUMARATE Seroquel RISPERIDONE Rispiradal RIZATRIPTAN BENZOATE Maxalt SALICYLAMIDE bc powder SUMATRIPTAN Imitrex Sumatriptan TETRAZEPAM Tetrazepam TOPIRAMATE topamax TRAMADOL HYDROCHLORIDE Tramacet VENLAFAXINE HYDROCHLORIDE Effexor ZOLMITRIPTAN Zomig ZOLPIDEM TARTRATE Ambien

Protocol: FFU111439 Population: Intent-to-Treat

Page 21 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

CONFIDENTIAL

227

RM2008/00422/00

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM DEXTROMETHORPHAN HYDROBROMIDE Nyquil robitussin DM DIPHENHYDRAMINE Excedrin PM diphenhydramine DIPHENHYDRAMINE CITRATE Advil PM DIPHENHYDRAMINE HYDROCHLORIDE Simply Sleep DOXYLAMINE SUCCINATE NyQuil Nyquil FORMOTEROL FUMARATE Symbicort GUAIFENESIN Mucinex robitussin DM HYDROCODONE hydrocodone/ acetamenophen HYDROCODONE BITARTRATE Norco KETOTIFEN FUMARATE Zaditor LEVOCETIRIZINE HYDROCHLORIDE Xyzal LEVOMENTHOL Bilagit Septolete LIDOCAINE Lidocain 1% LORATADINE Claritin claritin D MOMETASONE FUROATE Nasonex MONTELUKAST SODIUM Singulair Multiple Ingredient Advil PM NyQuil Nyquil Septolete Symbicort claritin D hydrocodone/ acetamenophen robitussin DM NAPHAZOLINE HYDROCHLORIDE clear eyes OXYMETAZOLINE HYDROCHLORIDE Afrin POTASSIUM IODIDE JodThyroxin 75/100 Thyronaiod

Protocol: FFU111439 Population: Intent-to-Treat

Page 22 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

SENSORY ORGANS

228

SODIUM CHLORIDE TETRYZOLINE HYDROCHLORIDE

Apple Cider Vinegar Acetylcystein Acyclovir Ciprofloxacin Clonidine Diclofenac Lioton Gel (Heparin) Bilagit Zaditor Lidocain 1% clear eyes Patanol 0.1% Afrin JodThyroxin 75/100 Thyronaiod NASAL SALINE Visine Original

BETAMETHASONE DIPROPIONATE

Lotricomb Creme

BUDESONIDE

Rhinocort aqua

RM2008/00422/00

SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS

ACETIC ACID ACETYLCYSTEINE ACYCLOVIR CIPROFLOXACIN CLONIDINE DICLOFENAC HEPARIN SODIUM HOMATROPINE METHYLBROMIDE KETOTIFEN FUMARATE LIDOCAINE NAPHAZOLINE HYDROCHLORIDE OLOPATADINE HYDROCHLORIDE OXYMETAZOLINE HYDROCHLORIDE POTASSIUM IODIDE

CONFIDENTIAL

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM PSEUDOEPHEDRINE HYDROCHLORIDE NyQuil Nyquil Pseudofed PSEUDOEPHEDRINE SULFATE claritin D SALBUTAMOL ALBUTEROL Albuterol Salbutamol Ventolin albuterol SALBUTAMOL SULFATE Proventil HFA SODIUM CHLORIDE NASAL SALINE TETRYZOLINE HYDROCHLORIDE Visine Original

Protocol: FFU111439 Population: Intent-to-Treat

Page 23 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

VARIOUS

ACETYLCYSTEINE ALLERGENS (NOS) ALLIUM SATIVUM AMBIGUOUS MEDICATION CUCURBITA PEPO

RM2008/00422/00

EUCALYPTUS GLOBULUS OIL LINOLENIC ACID LINUM USITATISSIMUM LINUM USITATISSIMUM OIL

Acetylcystein Allergy Immunotherapy Garlic Reactine Granu Fink Prosta ingredients: Medical Cucurbita and Saegepalmenfrucht (Sabal) - English unknown Septolete Omega 369 Flax Flax seed oil flax seed oil

CONFIDENTIAL

229

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------SYSTEMIC HORMONAL PREPARATIONS, EXCL. BUDESONIDE Symbicort SEX HORMONES AND INSULINS LEVOTHYROXINE Levothyroxin Levothyroxine Levthyroxine LEVOTHYROXINE SODIUM Euthyrox JodThyroxin 75/100 L-Thyroxin L-Tyhroxine Snythroid Synthroid Thyronaiod synthroid sythroid Multiple Ingredient JodThyroxin 75/100 Thyronaiod POTASSIUM IODIDE JodThyroxin 75/100 Thyronaiod THYROID Armour dessicated thyroid

Protocol: FFU111439 Population: Intent-to-Treat

Page 24 of 24

Table 6.24 Relationship of ATC Level 1, Ingredients, and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ---------------------------------------------------------------------------------------------------VARIOUS MONASCUS PURPUREUS red yeast rice Multiple Ingredient Omega 369 OLEIC ACID Omega 369 POTASSIUM IODIDE JodThyroxin 75/100 Thyronaiod VACCINIUM MACROCARPON cranberry tablets

CONFIDENTIAL

230

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------Any Medication 81 (52%) 86 (54%) 167 (53%) (25%) (13%) (10%) (3%) (2%) (3%) (1%) (1%) (1%) (<1%) (<1%) (1%) (1%) (<1%) (1%) (1%) (<1%) (<1%) (<1%) (<1%)

(<1%)

45 18 21 4 5 2 3 2 2 2 3 2 1 1 1 0 0 1 0 0 0 0 1 1 1 0 1 1 1

(28%) (11%) (13%) (3%) (3%) (1%) (2%) (1%) (1%) (1%) (2%) (1%) (<1%) (<1%) (<1%) (<1%)

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

84 38 37 9 8 7 5 4 4 3 3 3 3 3 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1

(27%) (12%) (12%) (3%) (3%) (2%) (2%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

39 20 16 5 3 5 2 2 2 1 0 1 2 2 1 2 2 0 1 1 1 1 0 0 0 1 0 0 0

CONFIDENTIAL

231

GENITO URINARY SYSTEM AND SEX HORMONES Any Medication IBUPROFEN ETHINYLOESTRADIOL NORGESTIMATE DESOGESTREL LEVONORGESTREL MEDROXYPROGESTERONE ACETATE NAPROXEN NAPROXEN SODIUM CYPROTERONE ACETATE DIENOGEST DROSPIRENONE METRONIDAZOLE NORETHISTERONE ESTRADIOL ESTROGENS ESTERIFIED METHYLTESTOSTERONE ACETIC ACID CLOTRIMAZOLE CUCURBITA PEPO ESTROGENS CONJUGATED ETONOGESTREL GESTODENE HORMONE REPLACEMENT THERAPY (NOS) MAGNESIUM HYDROXIDE MEDROXYPROGESTERONE NORELGESTROMIN NORETHISTERONE ACETATE PROGESTERONE

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------SERENOA REPENS 1 (<1%) 0 1 (<1%) VACCINIUM MACROCARPON 1 (<1%) 0 1 (<1%) (29%) (13%) (9%) (5%) (2%) (1%) (1%) (2%) (2%) (<1%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

39 18 9 14 1 2 1 0 0 1 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0

(24%) (11%) (6%) (9%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%)

84 38 23 22 4 4 3 3 3 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1

(27%) (12%) (7%) (7%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

45 20 14 8 3 2 2 3 3 1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

CONFIDENTIAL

232

NERVOUS SYSTEM Any Medication IBUPROFEN PARACETAMOL ACETYLSALICYLIC ACID CAFFEINE ZOLPIDEM TARTRATE ALPRAZOLAM CITALOPRAM HYDROBROMIDE PREGABALIN BUPROPION HYDROCHLORIDE CITALOPRAM OXYCODONE RIZATRIPTAN BENZOATE SUMATRIPTAN BUPROPION CLONIDINE CODEINE DEXTROPROPOXYPHENE NAPSILATE DULOXETINE HYDROCHLORIDE ESCITALOPRAM OXALATE ESZOPICLONE FLUOXETINE HYDROCHLORIDE GABAPENTIN LORAZEPAM MIRTAZAPINE PAROXETINE HYDROCHLORIDE QUETIAPINE FUMARATE RISPERIDONE

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------SALICYLAMIDE 1 (<1%) 0 1 (<1%) TOPIRAMATE 1 (<1%) 0 1 (<1%) VENLAFAXINE HYDROCHLORIDE 1 (<1%) 0 1 (<1%) ZOLMITRIPTAN 0 1 (<1%) 1 (<1%) (27%) (13%) (5%) (6%) (2%) (3%) (<1%) (1%) (1%) (1%) (1%) (<1%) (1%) (1%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%)

36 14 14 3 5 0 2 3 1 1 1 1 1 0 0 2 1 0 1 0 0 1 0 1 0 0

(23%) (9%) (9%) (2%) (3%) (1%) (2%) (<1%) (<1%) (<1%) (<1%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%)

78 34 22 13 8 4 3 3 3 3 3 3 2 2 2 2 2 2 1 1 1 1 1 1 1 1

(25%) (11%) (7%) (4%) (3%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

42 20 8 10 3 4 1 0 2 2 2 2 1 2 2 0 1 2 0 1 1 0 1 0 1 1

CONFIDENTIAL

233

ALIMENTARY TRACT AND METABOLISM Any Medication VITAMINS NOS ACETYLSALICYLIC ACID CALCIUM OMEPRAZOLE METFORMIN ASCORBIC ACID CALCIUM CARBONATE ERGOCALCIFEROL MESALAZINE METRONIDAZOLE PANTOPRAZOLE ESOMEPRAZOLE MAGNESIUM LANSOPRAZOLE MAGNESIUM RANITIDINE HYDROCHLORIDE TOCOPHEROL VITAMIN D NOS ALUMINIUM HYDROXIDE GEL, DRIED BALSALAZIDE SODIUM BETAMETHASONE DIPROPIONATE CALCIUM D3 (NOS) CLOTRIMAZOLE DIMETICONE, ACTIVATED DULCOLAX (NOS) INSULIN ASPART

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

234 Note:

32 20 8 2 2 2 1 1 0 1 1 1 0 1 0 0

(21%) (13%) (5%) (1%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

36 18 14 2 2 1 1 0 1 0 0 0 1 0 1 1

(23%) (11%) (9%) (1%) (1%) (<1%) (<1%) (<1%)

(<1%) (<1%) (<1%)

68 38 22 4 4 3 2 1 1 1 1 1 1 1 1 1

(22%) (12%) (7%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

MUSCULO-SKELETAL SYSTEM Any Medication IBUPROFEN ACETYLSALICYLIC ACID NAPROXEN NAPROXEN SODIUM GLUCOSAMINE ALLOPURINOL ALENDRONATE SODIUM CARISOPRODOL CELECOXIB COLCHICINE DICLOFENAC MELOXICAM RISEDRONATE SODIUM SODIUM IBANDRONATE SULINDAC

CONFIDENTIAL

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------INSULIN DETEMIR 1 (<1%) 0 1 (<1%) INSULIN LISPRO 1 (<1%) 0 1 (<1%) LINUM USITATISSIMUM 1 (<1%) 0 1 (<1%) LOPERAMIDE HYDROCHLORIDE 0 1 (<1%) 1 (<1%) MAGNESIUM HYDROXIDE 0 1 (<1%) 1 (<1%) METFORMIN HYDROCHLORIDE 0 1 (<1%) 1 (<1%) MINERALS NOS 1 (<1%) 0 1 (<1%) PROBIOTICS (NOS) 1 (<1%) 0 1 (<1%) PYRIDOXINE HYDROCHLORIDE 1 (<1%) 0 1 (<1%) SITAGLIPTIN 1 (<1%) 0 1 (<1%) SWEET OIL 1 (<1%) 0 1 (<1%) ZINC 0 1 (<1%) 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

235 Note:

21 3 2 4 1 2 2 2 1 1 1 0 1 1 0 1 1 1 0

(14%) (2%) (1%) (3%) (<1%) (1%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

17 3 4 0 3 1 1 1 1 1 1 2 1 0 1 0 0 0 1

(11%) (2%) (3%) (2%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (1%) (<1%) (<1%)

(<1%)

38 6 6 4 4 3 3 3 2 2 2 2 2 1 1 1 1 1 1

(12%) (2%) (2%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

CARDIOVASCULAR SYSTEM Any Medication FISH OIL HYDROCHLOROTHIAZIDE LISINOPRIL SIMVASTATIN ATORVASTATIN CALCIUM CANDESARTAN CILEXETIL METOPROLOL BENAZEPRIL HYDROCHLORIDE IRBESARTAN METOPROLOL TARTRATE OMEGA-3 MARINE TRIGLYCERIDES ROSUVASTATIN CALCIUM AMLODIPINE BESILATE ATENOLOL BETAMETHASONE DIPROPIONATE CARVEDILOL CLONIDINE DILTIAZEM HYDROCHLORIDE

CONFIDENTIAL

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS Any Medication 24 (15%) 32 (20%) 56 (18%) ETHINYLOESTRADIOL 16 (10%) 21 (13%) 37 (12%) IMMUNOTHERAPY{NOS} 3 (2%) 8 (5%) 11 (3%) MEDROXYPROGESTERONE ACETATE 2 (1%) 3 (2%) 5 (2%) ESTRADIOL 1 (<1%) 1 (<1%) 2 (<1%) ESTROGENS ESTERIFIED 2 (1%) 0 2 (<1%) ESTROGENS CONJUGATED 1 (<1%) 0 1 (<1%) MEDROXYPROGESTERONE 1 (<1%) 0 1 (<1%) METHOTREXATE 0 1 (<1%) 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

18 15 1 1 1 1 0 0

(12%) (10%) (<1%) (<1%) (<1%) (<1%)

BLOOD AND BLOOD FORMING ORGANS Any Medication ACETYLSALICYLIC ACID

12 8

(8%) (5%)

16 13 1 0 0 0 1 1

(10%) (8%) (<1%)

(<1%) (<1%)

18 (11%) 14 (9%)

34 28 2 1 1 1 1 1

(11%) (9%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

30 (10%) 22 (7%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

RESPIRATORY SYSTEM Any Medication SALBUTAMOL POTASSIUM IODIDE BETAMETHASONE DIPROPIONATE CODEINE HYDROCODONE BITARTRATE SALBUTAMOL SULFATE TETRYZOLINE HYDROCHLORIDE

CONFIDENTIAL

236

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------ENALAPRIL 1 (<1%) 0 1 (<1%) ENALAPRIL MALEATE 0 1 (<1%) 1 (<1%) EZETIMIBE 0 1 (<1%) 1 (<1%) FUROSEMIDE 0 1 (<1%) 1 (<1%) HEPARIN SODIUM 0 1 (<1%) 1 (<1%) METOPROLOL SUCCINATE 0 1 (<1%) 1 (<1%) MONASCUS PURPUREUS 1 (<1%) 0 1 (<1%) MOXONIDINE 1 (<1%) 0 1 (<1%) NICOTINIC ACID 0 1 (<1%) 1 (<1%) OLMESARTAN 0 1 (<1%) 1 (<1%) PERINDOPRIL 1 (<1%) 0 1 (<1%) QUINAPRIL 0 1 (<1%) 1 (<1%) RAMIPRIL 0 1 (<1%) 1 (<1%) TELMISARTAN 0 1 (<1%) 1 (<1%) TRANDOLAPRIL 1 (<1%) 0 1 (<1%) TRIAMTERENE 0 1 (<1%) 1 (<1%) VALSARTAN 1 (<1%) 0 1 (<1%) VERAPAMIL 0 1 (<1%) 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------FOLIC ACID 1 (<1%) 3 (2%) 4 (1%) CYANOCOBALAMIN 2 (1%) 0 2 (<1%) FERROUS GLUCONATE 0 1 (<1%) 1 (<1%) FERROUS SULPHATE 0 1 (<1%) 1 (<1%) HEPARIN SODIUM 0 1 (<1%) 1 (<1%) IRON 1 (<1%) 0 1 (<1%) PHENPROCOUMON 0 1 (<1%) 1 (<1%) UREA 1 (<1%) 0 1 (<1%)

8 2 0 1 1 1 1 1 1 1 1

(5%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

6 (4%) 4 (3%) 2 (1%) 1 (<1%) 0 0

18 (6%) 11 (3%) 4 (1%) 2 (<1%) 2 (<1%) 1 (<1%)

4 (3%) 1 (<1%) 2 (1%) 1 (<1%) 0 0 0 0 0 0 0

12 3 2 2 1 1 1 1 1 1 1

(4%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

DERMATOLOGICALS Note:

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

VARIOUS Any Medication LINUM USITATISSIMUM OIL ALLERGENS (NOS) POTASSIUM IODIDE ALLIUM SATIVUM CUCURBITA PEPO LINOLENIC ACID LINUM USITATISSIMUM MONASCUS PURPUREUS OLEIC ACID VACCINIUM MACROCARPON

12 (8%) 7 (5%) 2 (1%) 1 (<1%) 2 (1%) 1 (<1%)

CONFIDENTIAL

237

SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS Any Medication LEVOTHYROXINE SODIUM LEVOTHYROXINE POTASSIUM IODIDE THYROID BETAMETHASONE DIPROPIONATE

Protocol: FFU111439 Population: Intent-to-Treat

Page 8 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

238

3 (2%) 2 (1%) 0 0 0 0 0 1 (<1%)

6 1 2 1 1 1 1 0

(4%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%)

9 3 2 1 1 1 1 1

(3%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

SENSORY ORGANS Any Medication POTASSIUM IODIDE ACETIC ACID ACYCLOVIR CLONIDINE DICLOFENAC HEPARIN SODIUM TETRYZOLINE HYDROCHLORIDE

3 (2%) 1 (<1%) 0 0 1 (<1%) 1 (<1%) 0 0

5 1 1 1 0 0 1 1

(3%) (<1%) (<1%) (<1%)

8 2 1 1 1 1 1 1

(3%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

(<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

ANTIINFECTIVES FOR SYSTEMIC USE Any Medication METRONIDAZOLE TRIMETHOPRIM ACYCLOVIR CEFALEXIN HUMAN PAPILLOMA VIRUS VACCINE SULFAMETHOXAZOLE VALACICLOVIR HYDROCHLORIDE

CONFIDENTIAL

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------Any Medication 7 (5%) 4 (3%) 11 (3%) METRONIDAZOLE 2 (1%) 1 (<1%) 3 (<1%) TOCOPHEROL 1 (<1%) 1 (<1%) 2 (<1%) ACYCLOVIR 0 1 (<1%) 1 (<1%) AZELAIC ACID 0 1 (<1%) 1 (<1%) BETAMETHASONE DIPROPIONATE 1 (<1%) 0 1 (<1%) CLOBETASOL PROPIONATE 1 (<1%) 0 1 (<1%) CLOTRIMAZOLE 1 (<1%) 0 1 (<1%) LINOLEIC ACID 1 (<1%) 0 1 (<1%) UREA 1 (<1%) 0 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 9 of 9

Table 6.25 Summary of Concomitant Medications During the Screening Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS Any Medication 3 (2%) 1 (<1%) 4 (1%) METRONIDAZOLE 2 (1%) 1 (<1%) 3 (<1%) CUCURBITA PEPO 1 (<1%) 0 1 (<1%)

CONFIDENTIAL

239 A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------Any Medication 93 (60%) 104 (65%) 197 (63%) (34%) (14%) (11%) (8%) (3%) (1%) (1%) (2%) (2%) (<1%) (<1%) (<1%) (<1%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

55 26 18 17 2 2 1 0 0 2 1 1 1 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0

(34%) (16%) (11%) (11%) (1%) (1%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%)

(<1%)

108 48 35 29 6 4 3 3 3 3 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1

(34%) (15%) (11%) (9%) (2%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

53 22 17 12 4 2 2 3 3 1 1 1 1 2 2 1 1 1 1 1 0 1 1 1 1 1 1 1 1

CONFIDENTIAL

240

NERVOUS SYSTEM Any Medication IBUPROFEN PARACETAMOL ACETYLSALICYLIC ACID CAFFEINE ZOLPIDEM TARTRATE ALPRAZOLAM CITALOPRAM HYDROBROMIDE PREGABALIN SUMATRIPTAN BUPROPION HYDROCHLORIDE CITALOPRAM GABAPENTIN OXYCODONE PAROXETINE HYDROCHLORIDE RIZATRIPTAN BENZOATE BUPROPION CITRAMON (NOS) CLONIDINE DEXTROPROPOXYPHENE NAPSILATE DIAZEPAM DOXYLAMINE SUCCINATE DULOXETINE HYDROCHLORIDE ESZOPICLONE FLUOXETINE HYDROCHLORIDE LIDOCAINE LORAZEPAM MEFENAMIC ACID MIRTAZAPINE

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------QUETIAPINE FUMARATE 1 (<1%) 0 1 (<1%) RISPERIDONE 1 (<1%) 0 1 (<1%) SALICYLAMIDE 1 (<1%) 0 1 (<1%) TETRAZEPAM 1 (<1%) 0 1 (<1%) TOPIRAMATE 1 (<1%) 0 1 (<1%) TRAMADOL HYDROCHLORIDE 0 1 (<1%) 1 (<1%) VENLAFAXINE HYDROCHLORIDE 1 (<1%) 0 1 (<1%) ZOLMITRIPTAN 0 1 (<1%) 1 (<1%) (26%) (14%) (10%) (3%) (2%) (3%) (1%) (1%) (1%) (<1%) (<1%) (1%) (1%) (<1%) (1%) (1%) (<1%) (<1%) (<1%)

55 26 21 4 5 2 3 2 2 2 3 2 1 1 1 0 0 1 1 0 0 0

(34%) (16%) (13%) (3%) (3%) (1%) (2%) (1%) (1%) (1%) (2%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%)

95 48 37 9 8 7 5 4 4 3 3 3 3 3 2 2 2 1 1 1 1 1

(30%) (15%) (12%) (3%) (3%) (2%) (2%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

40 22 16 5 3 5 2 2 2 1 0 1 2 2 1 2 2 0 0 1 1 1

CONFIDENTIAL

241

GENITO URINARY SYSTEM AND SEX HORMONES Any Medication IBUPROFEN ETHINYLOESTRADIOL NORGESTIMATE DESOGESTREL LEVONORGESTREL MEDROXYPROGESTERONE ACETATE NAPROXEN NAPROXEN SODIUM CYPROTERONE ACETATE DIENOGEST DROSPIRENONE METRONIDAZOLE NORETHISTERONE ESTRADIOL ESTROGENS ESTERIFIED METHYLTESTOSTERONE ACETIC ACID CLINDAMYCIN CLOTRIMAZOLE CUCURBITA PEPO ESTROGENS CONJUGATED

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

242 Note:

50 20 12 10 4 2 4 0 2 2 2 2 1 2 2 0 2 1

(32%) (13%) (8%) (6%) (3%) (1%) (3%) (1%) (1%) (1%) (1%) (<1%) (1%) (1%) (1%) (<1%)

44 14 17 3 5 3 0 3 1 1 1 1 1 0 0 2 0 1

(28%) (9%) (11%) (2%) (3%) (2%) (2%) (<1%) (<1%) (<1%) (<1%) (<1%) (1%) (<1%)

94 34 29 13 9 5 4 3 3 3 3 3 2 2 2 2 2 2

(30%) (11%) (9%) (4%) (3%) (2%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

ALIMENTARY TRACT AND METABOLISM Any Medication VITAMINS NOS ACETYLSALICYLIC ACID CALCIUM OMEPRAZOLE ASCORBIC ACID METFORMIN CALCIUM CARBONATE ERGOCALCIFEROL MESALAZINE METRONIDAZOLE PANTOPRAZOLE ESOMEPRAZOLE MAGNESIUM LANSOPRAZOLE MAGNESIUM RANITIDINE HYDROCHLORIDE RETINOL ACETATE TOCOPHEROL

CONFIDENTIAL

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------ETONOGESTREL 1 (<1%) 0 1 (<1%) GESTODENE 0 1 (<1%) 1 (<1%) HORMONE REPLACEMENT THERAPY (NOS) 0 1 (<1%) 1 (<1%) LACTIC ACID 0 1 (<1%) 1 (<1%) MAGNESIUM HYDROXIDE 0 1 (<1%) 1 (<1%) MEDROXYPROGESTERONE 1 (<1%) 0 1 (<1%) NORELGESTROMIN 0 1 (<1%) 1 (<1%) NORETHISTERONE ACETATE 0 1 (<1%) 1 (<1%) PAPAVERINE HYDROCHLORIDE 0 1 (<1%) 1 (<1%) PROGESTERONE 0 1 (<1%) 1 (<1%) SERENOA REPENS 1 (<1%) 0 1 (<1%) VACCINIUM MACROCARPON 1 (<1%) 0 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

CONFIDENTIAL

243

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------VITAMIN D NOS 2 (1%) 0 2 (<1%) ALUMINIUM HYDROXIDE GEL, DRIED 0 1 (<1%) 1 (<1%) BALSALAZIDE SODIUM 1 (<1%) 0 1 (<1%) BETAMETHASONE DIPROPIONATE 1 (<1%) 0 1 (<1%) BILE 0 1 (<1%) 1 (<1%) BISMUTH SUBSALICYLATE 1 (<1%) 0 1 (<1%) BUDESONIDE 1 (<1%) 0 1 (<1%) CALCIUM D3 (NOS) 0 1 (<1%) 1 (<1%) CLOTRIMAZOLE 1 (<1%) 0 1 (<1%) DIMETICONE, ACTIVATED 0 1 (<1%) 1 (<1%) DROTAVERINE 0 1 (<1%) 1 (<1%) GASTRIC MUCOUS MEMBRANE EXTRACT 0 1 (<1%) 1 (<1%) INSULIN ASPART 1 (<1%) 0 1 (<1%) INSULIN DETEMIR 1 (<1%) 0 1 (<1%) INSULIN LISPRO 1 (<1%) 0 1 (<1%) LACTIC ACID 0 1 (<1%) 1 (<1%) LACTIC-ACID-PRODUCING ORGANISMS 0 1 (<1%) 1 (<1%) LINUM USITATISSIMUM 1 (<1%) 0 1 (<1%) LOPERAMIDE HYDROCHLORIDE 0 1 (<1%) 1 (<1%) MAGNESIUM HYDROXIDE 0 1 (<1%) 1 (<1%) METFORMIN HYDROCHLORIDE 0 1 (<1%) 1 (<1%) MINERALS NOS 1 (<1%) 0 1 (<1%) MUNDISAL (NOS) 0 1 (<1%) 1 (<1%) PAPAVERINE HYDROCHLORIDE 0 1 (<1%) 1 (<1%) PHENOLPHTHALEIN 0 1 (<1%) 1 (<1%) PROBIOTICS (NOS) 1 (<1%) 0 1 (<1%) PYRIDOXINE HYDROCHLORIDE 1 (<1%) 0 1 (<1%) RANITIDINE 0 1 (<1%) 1 (<1%) SITAGLIPTIN 1 (<1%) 0 1 (<1%) SWEET OIL 1 (<1%) 0 1 (<1%) ZINC 0 1 (<1%) 1 (<1%) ZINC GLUCONATE 0 1 (<1%) 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------(26%) (14%) (8%) (1%) (1%) (1%) (<1%) (1%)

(<1%)

46 26 17 2 2 1 1 0 2 2 0 1 0 0 0 0 1 1 0

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS Any Medication ETHINYLOESTRADIOL IMMUNOTHERAPY{NOS} MEDROXYPROGESTERONE ACETATE ESTRADIOL ESTROGENS ESTERIFIED ESTROGENS CONJUGATED MEDROXYPROGESTERONE

24 16 3 2 1 2 1 1

(15%) (10%) (2%) (1%) (<1%) (1%) (<1%) (<1%)

32 (20%) 21 (13%) 8 (5%) 3 (2%) 1 (<1%) 0 0 0

(<1%) (<1%) (<1%) (<1%) (<1%)

(29%) (16%) (11%) (1%) (1%) (<1%) (<1%) (1%) (1%) (<1%)

(<1%) (<1%)

86 48 29 4 4 3 2 2 2 2 1 1 1 1 1 1 1 1 1

(27%) (15%) (9%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

56 37 11 5 2 2 1 1

(18%) (12%) (3%) (2%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

40 22 12 2 2 2 1 2 0 0 1 0 1 1 1 1 0 0 1

CONFIDENTIAL

244 Note:

MUSCULO-SKELETAL SYSTEM Any Medication IBUPROFEN ACETYLSALICYLIC ACID NAPROXEN NAPROXEN SODIUM GLUCOSAMINE ALLOPURINOL DICLOFENAC LEVOMENTHOL MELOXICAM ALENDRONATE SODIUM CARISOPRODOL CELECOXIB COLCHICINE MEFENAMIC ACID RISEDRONATE SODIUM SODIUM IBANDRONATE SULINDAC TETRAZEPAM

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------METHOTREXATE 0 1 (<1%) 1 (<1%) (16%) (2%) (1%) (2%) (3%) (<1%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

(<1%) (<1%) (<1%)

17 3 4 1 0 3 1 1 1 1 1 2 1 0 1 0 0 0 0 1 0 1 1 1 1 0 0 1 0

(11%) (2%) (3%) (<1%) (2%) (<1%) (<1%) (<1%) (<1%) (<1%) (1%) (<1%) (<1%)

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

42 6 6 4 4 4 3 3 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

(13%) (2%) (2%) (1%) (1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

25 3 2 3 4 1 2 2 1 1 1 0 1 1 0 1 1 1 1 0 1 0 0 0 0 1 1 0 1

CONFIDENTIAL

245

CARDIOVASCULAR SYSTEM Any Medication FISH OIL HYDROCHLOROTHIAZIDE ATORVASTATIN CALCIUM LISINOPRIL SIMVASTATIN CANDESARTAN CILEXETIL METOPROLOL BENAZEPRIL HYDROCHLORIDE IRBESARTAN METOPROLOL TARTRATE OMEGA-3 MARINE TRIGLYCERIDES ROSUVASTATIN CALCIUM AMLODIPINE BESILATE ATENOLOL BETAMETHASONE DIPROPIONATE CARVEDILOL CLONIDINE DILTIAZEM DILTIAZEM HYDROCHLORIDE ENALAPRIL ENALAPRIL MALEATE EZETIMIBE FUROSEMIDE HEPARIN SODIUM INDAPAMIDE LIDOCAINE METOPROLOL SUCCINATE MONASCUS PURPUREUS

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

246 Note:

21 15 1 0 1 1 0 0 0 1 1 1 1 0 1 1 1 0

(14%) (10%) (<1%) (<1%) (<1%)

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

20 13 1 2 1 0 1 1 1 0 0 0 0 1 0 0 0 1

(13%) (8%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%)

(<1%)

(<1%)

41 28 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1

(13%) (9%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

RESPIRATORY SYSTEM Any Medication SALBUTAMOL DEXTROMETHORPHAN HYDROBROMIDE LEVOMENTHOL POTASSIUM IODIDE ACETYLCYSTEINE AMBAZONE AMBROXOL HYDROCHLORIDE BENZALKONIUM CHLORIDE BETAMETHASONE DIPROPIONATE BUDESONIDE DOXYLAMINE SUCCINATE FORMOTEROL FUMARATE GUAIFENESIN HYDROCODONE BITARTRATE LIDOCAINE PSEUDOEPHEDRINE HYDROCHLORIDE SALBUTAMOL SULFATE

CONFIDENTIAL

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------MOXONIDINE 1 (<1%) 0 1 (<1%) NICOTINIC ACID 0 1 (<1%) 1 (<1%) OLMESARTAN 0 1 (<1%) 1 (<1%) PERINDOPRIL 1 (<1%) 0 1 (<1%) QUINAPRIL 0 1 (<1%) 1 (<1%) RAMIPRIL 0 1 (<1%) 1 (<1%) TELMISARTAN 0 1 (<1%) 1 (<1%) TRANDOLAPRIL 1 (<1%) 0 1 (<1%) TRIAMTERENE 0 1 (<1%) 1 (<1%) VALSARTAN 1 (<1%) 0 1 (<1%) VERAPAMIL 0 1 (<1%) 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 8 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

247 Note:

10 3 2 0 1 0 0 1 0 1 1 0 0 1 1 0 0 1

(6%) (2%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

11 0 1 2 1 1 1 0 1 0 0 1 1 0 0 1 1 0

(7%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

21 3 3 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1

(7%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

ANTIINFECTIVES FOR SYSTEMIC USE Any Medication CLARITHROMYCIN METRONIDAZOLE AZITHROMYCIN CEFALEXIN ACYCLOVIR AMOXICILLIN AMOXICILLIN TRIHYDRATE CEFUROXIME CIPROFLOXACIN CLAVULANATE POTASSIUM CLINDAMYCIN METHENAMINE MOXIFLOXACIN PNEUMOCOCCAL VACCINE TETANUS TOXOID TRIMETHOPRIM VALACICLOVIR HYDROCHLORIDE

CONFIDENTIAL

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------BLOOD AND BLOOD FORMING ORGANS Any Medication 17 (11%) 22 (14%) 39 (12%) ACETYLSALICYLIC ACID 12 (8%) 17 (11%) 29 (9%) FOLIC ACID 2 (1%) 3 (2%) 5 (2%) CYANOCOBALAMIN 2 (1%) 0 2 (<1%) AMINO ACIDS NOS 0 1 (<1%) 1 (<1%) FERROUS GLUCONATE 0 1 (<1%) 1 (<1%) FERROUS SULPHATE 0 1 (<1%) 1 (<1%) HEPARIN SODIUM 0 1 (<1%) 1 (<1%) IRON 1 (<1%) 0 1 (<1%) PHENPROCOUMON 0 1 (<1%) 1 (<1%) UREA 1 (<1%) 0 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 9 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ----------------------------------------------------------------------------------------

248

DERMATOLOGICALS Any Medication METRONIDAZOLE LEVOMENTHOL TOCOPHEROL ACYCLOVIR AZELAIC ACID BENZALKONIUM CHLORIDE BETAMETHASONE DIPROPIONATE BUDESONIDE CLINDAMYCIN CLOBETASOL PROPIONATE CLOTRIMAZOLE LACTIC ACID LIDOCAINE LINOLEIC ACID THYMOL UREA

9 2 0 1 0 0 0 1 1 0 1 1 0 1 1 0 1

VARIOUS Any Medication

9

6 (4%) 4 (3%) 2 (1%) 1 (<1%) 0 0 0

19 11 4 2 2 1 1

(6%) (3%) (1%) (<1%) (<1%) (<1%) (<1%)

(5%) (<1%) (1%) (<1%) (<1%) (<1%) (<1%)

(<1%)

8 1 2 1 1 1 1 0 0 1 0 0 1 0 0 1 0

17 3 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1

(5%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

(6%)

5

(3%)

14

(4%)

(6%) (1%) (<1%)

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

(<1%) (<1%) (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

13 (8%) 7 (5%) 2 (1%) 1 (<1%) 2 (1%) 1 (<1%) 1 (<1%)

CONFIDENTIAL

SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS Any Medication LEVOTHYROXINE SODIUM LEVOTHYROXINE POTASSIUM IODIDE THYROID BETAMETHASONE DIPROPIONATE BUDESONIDE

Protocol: FFU111439 Population: Intent-to-Treat

Page 10 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

249

6 2 1 0 1 0 1 1 0 0 1

ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS Any Medication METRONIDAZOLE CUCURBITA PEPO

3 (2%) 2 (1%) 1 (<1%)

(4%) (1%) (<1%) (<1%) (<1%) (<1%) (<1%)

5 0 1 1 0 1 0 0 1 1 0

(3%) (<1%) (<1%) (<1%) (<1%) (<1%)

1 (<1%) 1 (<1%) 0

11 2 2 1 1 1 1 1 1 1 1

(3%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

4 (1%) 3 (<1%) 1 (<1%)

A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

SENSORY ORGANS Any Medication DICLOFENAC POTASSIUM IODIDE ACETIC ACID ACETYLCYSTEINE ACYCLOVIR CIPROFLOXACIN CLONIDINE HEPARIN SODIUM HOMATROPINE METHYLBROMIDE LIDOCAINE

CONFIDENTIAL

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------LINUM USITATISSIMUM OIL 2 (1%) 1 (<1%) 3 (<1%) ALLERGENS (NOS) 0 2 (1%) 2 (<1%) POTASSIUM IODIDE 1 (<1%) 1 (<1%) 2 (<1%) ACETYLCYSTEINE 1 (<1%) 0 1 (<1%) ALLIUM SATIVUM 1 (<1%) 0 1 (<1%) CUCURBITA PEPO 1 (<1%) 0 1 (<1%) EUCALYPTUS GLOBULUS OIL 0 1 (<1%) 1 (<1%) LINOLENIC ACID 1 (<1%) 0 1 (<1%) LINUM USITATISSIMUM 1 (<1%) 0 1 (<1%) MONASCUS PURPUREUS 1 (<1%) 0 1 (<1%) OLEIC ACID 1 (<1%) 0 1 (<1%) VACCINIUM MACROCARPON 1 (<1%) 0 1 (<1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 11 of 11

Table 6.26 Summary of Concomitant Medications During the Treatment Period

ATC Level 1 Placebo FF 110mcg QD Total Ingredient (N=155) (N=160) (N=315) ---------------------------------------------------------------------------------------Pharmacological properties cannot be referenced Any Medication 0 2 (1%) 2 (<1%) CHOLEINIC SODIUM 0 1 (<1%) 1 (<1%) DRY PANCREAS 0 1 (<1%) 1 (<1%)

CONFIDENTIAL

250 A medication may be included in more than one ATC Level Category and appear more than once.

RM2008/00422/00

Note:

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 181

Table 6.27 Listing of Concomitant Medications During the Study Period

Treatment: Placebo Inv./ Subj.

Study drug start/stop dates

ATC Level 1/ Ingredient/ Verbatim text

Study period

Date started/ Study day/ Route/ Date stopped Reason

Taken Prior to Study

Ongoing Medication?

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

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Page 1 of 1

Table 6.28 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record

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Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) -----------------------------------------------------------------------------Compliance rate - Weeks 1-4 n 155 160 315 Mean 98.7 101.1 99.9 SD 13.68 12.23 13.00 Median 103.3 103.4 103.4 Min. 10 71 10 Max. 133 200 200 Compliance rate category n 155 160 315 >=90% 133 (86%) 141 (88%) 274 (87%) >=80 - <90% 10 (6%) 12 (8%) 22 (7%) <80% 12 (8%) 7 (4%) 19 (6%)

RM2008/00422/00

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Efficacy Data Source Figures and Tables Page

Figure 7.1 Mean Daily Reflective Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

441

Figure 7.2 Mean Change from Baseline in Daily Reflective Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . .

442

Figure 7.3 Mean AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

443

Figure 7.4 Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . .

444

Figure 7.5 Mean Daily Reflective Total Ocular Symptom Scores Over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

445

Figure 7.6 Mean Change from Baseline in Daily Reflective Total Ocular Symptom Scores Over the Treatment Period . . . . . . . . . . . . . . . . . . . . .

446

Figure 7.7 Mean AM Reflective Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

447

Figure 7.8 Mean Change from Baseline in AM Reflective Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . .

448

Figure 7.9 Mean PM Reflective Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

449

Figure 7.10 Mean Change from Baseline in PM Reflective Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . .

450

Figure 7.11 Mean Percent Change from Baseline in Daily Reflective Total Nasal Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . .

451

Figure 7.12 Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period . .

452

Figure 7.13 Mean AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

453

Figure 7.14 Mean Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period . . . . . . . . . . . . .

454

Figure 7.15 Mean AM Reflective Total Ocular Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

455

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Figure 7.16 Mean Change from Baseline in AM Reflective Total Ocular Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . .

456

Figure 7.17 Mean PM Reflective Total Ocular Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

457

Figure 7.18 Mean Change from Baseline in PM Reflective Total Ocular Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . . . . . . . .

458

Figure 7.19 Mean Percent Change from Baseline in Daily Reflective Total Ocular Symptom Score over the Treatment Period . . . . . . . . . . . . . . . . .

459

Figure 7.20 Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period .

460

Table 7.1 Summary of Daily Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

461

Table 7.2 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . .

463

Table 7.3 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

465

Table 7.4 Analysis of Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . .

467

Table 7.5 Summary of Daily Reflective Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

469

Table 7.6 Analysis of Mean Change from Baseline in Daily Reflective Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . .

471

Table 7.7 Summary of AM Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

473

Table 7.8 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . .

475

Table 7.9 Summary of PM Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

477

Table 7.10 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . .

479

Table 7.11 Summary of Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . .

481

Table 7.12 Analysis of Mean Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores (Intent-to-Treat Population) . . .

483

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Table 7.13 Summary of Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

485

Table 7.14 Analysis of Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

487

Table 7.15 Summary of Daily Reflective Symptoms Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

489

Table 7.16 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . .

491

Table 7.17 Summary of Daily Reflective Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .

493

Table 7.18 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . .

495

Table 7.19 Summary of Daily Reflective Symptoms Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

497

Table 7.20 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . .

499

Table 7.21 Summary of Daily Reflective Symptom Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

501

Table 7.22 Analysis of Mean Change from Baseline in Daily Reflective Symptoms Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . .

503

Table 7.23 Summary of AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .

505

Table 7.24 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

507

Table 7.25 Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

509

Table 7.26 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

511

Table 7.27 Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .

513

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Table 7.28 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

515

Table 7.29 Summary of AM Pre-Dose Instantaneous Symptom Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

517

Table 7.30 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

519

Table 7.31 Summary of AM Reflective Symptom Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

521

Table 7.32 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . .

523

Table 7.33 Summary of AM Reflective Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .

525

Table 7.34 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . .

527

Table 7.35 Summary of AM Reflective Symptom Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

529

Table 7.36 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . .

531

Table 7.37 Summary of AM Reflective Symptom Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

533

Table 7.38 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . . .

535

Table 7.39 Summary of PM Reflective Symptom Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

537

Table 7.40 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Rhinorrhea (Intent-to-Treat Population) . . . . . . . . .

539

Table 7.41 Summary of PM Reflective Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .

541

Table 7.42 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Nasal Congestion (Intent-to-Treat Population) . . . .

543

Table 7.43 Summary of PM Reflective Symptom Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

545

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Table 7.44 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Nasal Itching (Intent-to-Treat Population) . . . . . . . .

547

Table 7.45 Summary of PM Reflective Symptom Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

549

Table 7.46 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Sneezing (Intent-to-Treat Population) . . . . . . . . . . .

551

Table 7.47 Summary of AM Pre-Dose Instantaneous Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

553

Table 7.48 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

555

Table 7.49 Summary of AM Reflective Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

557

Table 7.50 Analysis of Mean Change from Baseline in AM Reflective Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . .

559

Table 7.51 Summary of PM Reflective Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

561

Table 7.52 Analysis of Mean Change from Baseline in PM Reflective Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . .

563

Table 7.53 Summary of Daily Reflective Symptom Scores for Eye Itching/Burning (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .

565

Table 7.54 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Itching/Burning (Intent-to-Treat Population) . . .

567

Table 7.55 Summary of Daily Reflective Symptom Score for Eye Tearing/Watering (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

569

Table 7.56 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Tearing/Watering (Intent-to-Treat Population) .

571

Table 7.57 Summary of Daily Reflective Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

573

Table 7.58 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . .

575

Table 7.59 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . .

577

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Table 7.60 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

579

Table 7.61 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . .

581

Table 7.62 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

583

Table 7.63 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .

585

Table 7.64 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

587

Table 7.65 Summary of AM Reflective Symptom Scores for Eye Itching/Burning (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .

589

Table 7.66 Anlalysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Itching/Burning (Intent-to-Treat Population) . . .

591

Table 7.67 Summary of AM Reflective Symptom Scores for Eye Tearing/Watering (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

593

Table 7.68 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Tearing/Watering (Intent-to-Treat Population) .

595

Table 7.69 Summary of AM Reflective Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

597

Table 7.70 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . .

599

Table 7.71 Summary of PM Reflective Symptom Scores for Eye Itching/Burning (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .

601

Table 7.72 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Itching/Buring (Intent-to-Treat Population) . . . .

603

Table 7.73 Summary of PM Reflective Symptom Scores for Eye Tearing/Watering (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

605

Table 7.74 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Tearing/Watering (Intent-to-Treat Population) .

607

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Table 7.75 Summary of PM Reflective Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

609

Table 7.76 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Redness (Intent-to-Treat Population) . . . . . . . .

611

Table 7.77 Summary of Daily Peak Nasal Inspiratory Flow (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

613

Table 7.78 Analysis of Mean Change from Baseline in Daily Peak Nasal Inspiratory Flow (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .

615

Table 7.79 Summary of AM Peak Nasal Inspiratory Flow (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

617

Table 7.80 Analysis of Mean Change from Baseline in AM Peak Nasal Inspiratory Flow (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .

619

Table 7.81 Summary of PM Peak Nasal Inspiratory Flow (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

621

Table 7.82 Analysis of Mean Change from Baseline in PM Peak Nasal Inspiratory Flow (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .

623

Table 7.83 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

625

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

631

Table 7.85 Summary of Daily Reflective Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

638

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . .

644

Table 7.87 Summary of AM Reflective Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

651

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . .

657

Table 7.89 Summary of PM Reflective Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

664

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28 (Intent-to-Treat Population) . . . . . . . .

670

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Table 7.91 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Age 12 - <18 years Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

677

Table 7.92 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Age 18 - <65 years Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

679

Table 7.93 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Age >=65 years Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

681

Table 7.94 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/USA Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

683

Table 7.95 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Canada Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

685

Table 7.96 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Estonia Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

687

Table 7.97 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Slovakia Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

689

Table 7.98 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Germany Population). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

691

Table 7.99 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Hungary Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

693

Table 7.100 Summary of Daily Reflective Total Nasal Symptom Scores (ITT/Russian Federation Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

695

Table 7.101 Summary of Percent Change from Baseline in Daily Reflective Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . .

697

Table 7.102 Summary of Percent Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

699

440

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.1 Mean Daily Reflective Total Nasal Symptom Score over the Treatment Period 10.0 9.5 9.0

B A

8.0

B A

7.0 6.5 6.0 5.5 5.0

B A B A A A A A B A A B B A A A A B A A A A A A A B B B A A A A A B B B A B B B B B B B B B B B B B B

3

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A CONFIDENTIAL

441

Mean Daily rTNSS

8.5

B A

4.5 BL 1

2

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

Protocol: FFU111439 Population: Intent-to-Treat

0.0 -0.5

B A B A

-1.0

B A

-1.5

A B A B A A A A A A B A B B A A A A A A A A A A A B B B A A A A A B B B A B B B B B B B B B B B B B B B

-2.0 -2.5 -3.0 -3.5 -4.0

CONFIDENTIAL

442

Mean Change from Baseline in Daily rTNSS

Figure 7.2 Mean Change from Baseline in Daily Reflective Total Nasal Symptom Score over the Treatment Period

-4.5 -5.0 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.3 Mean AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period 10.0

9.0 8.5 8.0 7.5

B A B A B A

7.0 6.5 6.0 5.5 5.0

A A B A A A B B B A A A A A B B A A A A A A A A B B A A B B B A A A A A A B B B B B B B B B B B B B B B

CONFIDENTIAL

443

Mean AM Pre-Dose iTNSS

9.5

4.5 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat

0.0

B A

-0.5 -1.0

A B

B A

-1.5 -2.0 -2.5 -3.0 -3.5 -4.0

A A B A A A A A A A A B B B A A A A A B B A A A A B A A A A A A B A B B B B B B B B B B B B B B B B B B

CONFIDENTIAL

444

-4.5 -5.0 BL 1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

Mean Change from Baseline in AM Pre-Dose iTNSS

Figure 7.4 Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.5 Mean Daily Reflective Total Ocular Symptom Scores Over the Treatment Period 7.0 6.5

A B B A

5.5 5.0 4.5 4.0 3.5

A A B B A B A A A A A B B B B B A A A A A B B A A A A A A A B B B B B B A A A A A A B B B B B B B B B B

CONFIDENTIAL

445

Mean Daily rTOSS

6.0

A B

3.0 2.5 2.0 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat

0.0

B A

-0.5

B A B

-1.0

A

-2.0

-2.5

-3.0 BL 1

2

3

RM2008/00422/00

-1.5

B A B A B A B A A A B A A B B B A A A B A B A B A A A A A A B B A B B B A A A A A A B B B B B B B B B B

CONFIDENTIAL

446

Mean Change from Baseline in Daily rTOSS

Figure 7.6 Mean Change from Baseline in Daily Reflective Total Ocular Symptom Scores Over the Treatment Period

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.7 Mean AM Reflective Total Nasal Symptom Score over the Treatment Period 10.0 9.5 9.0

8.0

B A B A A

7.5

B A A A A A B B A A A B B A A A A A B B A A A A A A A B B A A A A B B A B B B B B B B B B B B B B B B

7.0 6.5 6.0 5.5 5.0

CONFIDENTIAL

447

Mean AM rTNSS

8.5

A B

4.5 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.8 Mean Change from Baseline in AM Reflective Total Nasal Symptom Score over the Treatment Period

-0.5 -1.0

B A B A B A A

-1.5

B A A A A A B B A A A B A A A A B A A A A B B A A A A A A B A B A B B A B B B B B B B B B B B B B B B

-2.0 -2.5 -3.0 -3.5 -4.0

CONFIDENTIAL

448

Mean Change from Baseline in AM rTNSS

0.0

-4.5 -5.0 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.9 Mean PM Reflective Total Nasal Symptom Score over the Treatment Period 10.0 9.5 9.0

B A

8.0

B A

7.0 6.5 6.0 5.5 5.0

A B B A A B A A A A A A A B B A A A A A A A B B B A A A B A A A B B A A A B B B B B B B B B B B B B B B

3

RM2008/00422/00

7.5

CONFIDENTIAL

449

Mean PM rTNSS

8.5

B A

4.5 BL 1

2

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.10 Mean Change from Baseline in PM Reflective Total Nasal Symptom Score over the Treatment Period

-0.5

B A B A B A

-1.0

A B A B A A A A A A B A A A A B B A A A A A A A A B A A B B A B A A A B B B B B B B B B B B B B B B B B

-1.5 -2.0 -2.5 -3.0 -3.5 -4.0

CONFIDENTIAL

450

Mean Change from Baseline in PM rTNSS

0.0

-4.5 -5.0 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat

0

B A

-5 -10

B A

B A

-15

A B A B A A A A A B A A A B B A A A A A A A A A A B B B A A A A A B B B A B B B B B B B B B B B B B B B

-20 -25 -30 -35 -40 -45

CONFIDENTIAL

451

Mean % Change from Baseline Daily rTNSS

Figure 7.11 Mean Percent Change from Baseline in Daily Reflective Total Nasal Symptom Score over the Treatment Period

-50 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat

0

B A

-5 -10

A B B A

-15

A

-20

B

A A A A A A A A B B B A A A A B B A A A A A A A A B A A A B A B B B B B B B B B B B B B B B B B B

3

4

-25 -30 -35 -40 -45

A

CONFIDENTIAL

452

-50 BL 1

2

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

Mean % Change from Baseline in AM Pre-Dose iTNSS

Figure 7.12 Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.13 Mean AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period 7.0

A B

6.0 5.5

B A B A A B

5.0 4.5 4.0

A A A B B B B A A A A B B B A A A A A B B A A A A A A B B B B A B A A A A A B B A B B B B B B B B B

3.5

CONFIDENTIAL

453

Mean AM Pre-Dose iTOSS

6.5

3.0 2.5 2.0 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat

0.0

-0.5

B A

B A B

-1.0

A

B A B A B A B A B A A A B A B B

-1.5

-2.0

A A A B A A A B B A A A A B B A B A B B B B B

A A A A A A B B B B B B B

-2.5

CONFIDENTIAL

454

-3.0 BL 1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

Mean Change from Baseline in AM Pre-Dose iTOSS

Figure 7.14 Mean Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.15 Mean AM Reflective Total Ocular Symptom Score over the Treatment Period 7.0 6.5

A B B A A B A A A A A B B A A B B A A A A A B B B A A A A A A A B B B B A A A A A B B B B B A B B B B B B B B B

5.5 5.0 4.5 4.0 3.5

CONFIDENTIAL

455

Mean AM rTOSS

6.0

A B

3.0 2.5 2.0 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.16 Mean Change from Baseline in AM Reflective Total Ocular Symptom Score over the Treatment Period

-0.5

B A

B A

-1.0

B A B A

-1.5

A B B A B A B A A

A A A B B A A A A B B A A A B B B A A A A B A A B B B A A B B A A B B B B B B B B

-2.0

-2.5

-3.0 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

CONFIDENTIAL

456

Mean Change from Baseline in AM rTOSS

0.0

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.17 Mean PM Reflective Total Ocular Symptom Score over the Treatment Period 7.0 6.5

A B B A

5.5

4.5 4.0 3.5

A A A A A B A A B B B A B A A A B A B A B A A A A B B B A A A A A A B B B A B B B B B B B B B B

5

RM2008/00422/00

A A B B

5.0

CONFIDENTIAL

457

Mean PM rTOSS

6.0

A B

3.0 2.5 2.0 BL 1

2

3

4

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

Protocol: FFU111439 Population: Intent-to-Treat Figure 7.18 Mean Change from Baseline in PM Reflective Total Ocular Symptom Score over the Treatment Period

-0.5

B A B A B

-1.0

A

-1.5 -2.0

B B A A B A A B B A A B A B A B

-2.5 -3.0

A A B A B A A A A A A B B A B A A B A B A A A A B B B A B B B B B B B B

CONFIDENTIAL

458

Mean Change from Baseline in PM rTOSS

0.0

-3.5 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat

0 -5 -10

B A B A

-15

B A B A B A B A A A A A B B A B B B A A A B A B A B A A A A B B A A A B B B A A A A A B B B A B B B B B B B

-20 -25 -30 -35 -40 -45

CONFIDENTIAL

459

Mean % Change from Baseline Daily rTOSS

Figure 7.19 Mean Percent Change from Baseline in Daily Reflective Total Ocular Symptom Score over the Treatment Period

-50 2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

RM2008/00422/00

BL 1

Protocol: FFU111439 Population: Intent-to-Treat

0 -5 -10

B A B A

-15

B A A B

-25 -30

A A A B B A A B B A B A A A A B B A B A A B B B A A A A A B B B A B B B B

4

RM2008/00422/00

-20

CONFIDENTIAL

460

Mean % Change from Baseline in AM Pre-Dose iTOSS

Figure 7.20 Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period

A A A A A A B B B B B B B

-35 -40 -45 -50 BL 1

2

3

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day

Treatment:

A A A

Placebo

B B B

FF 110mcg QD

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.1 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 9.1 (0.13) 9.1 (0.14) Median 9 8.9 Min - Max 6.0 - 12.0 3.5 - 12.0 155 -1.5 (0.16) -1.1 -9.6 - 3.9

160 7.4 (0.18) 7.5 0.9 - 12.0

160 -1.7 (0.15) -1.6 -8.9 - 2.2

Week 2 n Mean (Std Err) Median Min - Max

153 6.8 (0.21) 6.9 0.4 - 12.0

153 -2.3 (0.20) -1.9 -11.1 - 4.7

158 6.3 (0.22) 6.3 0.4 - 12.0

158 -2.9 (0.20) -2.6 -11.4 - 2.6

Week 3 n Mean (Std Err) Median Min - Max

151 6.5 (0.23) 6.7 0.0 - 12.0

151 -2.6 (0.22) -2.2 -9.8 - 5.1

156 5.6 (0.24) 5.5 0.0 - 12.0

156 -3.6 (0.23) -3.3 -11.1 - 2.2

Week 4 n Mean (Std Err) Median Min - Max

149 6.2 (0.24) 6.3 0.0 - 12.0

149 -2.9 (0.24) -2.4 -9.9 - 5.6

153 5.2 (0.25) 5.4 0.0 - 12.0

153 -4.0 (0.24) -3.9 -12.0 - 2.0

RM2008/00422/00

155 7.6 (0.19) 7.9 2.1 - 12.0

CONFIDENTIAL

461

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.1 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 6.9 (0.20) -2.2 (0.19) 6.1 (0.21) -3.0 (0.19) Median 7 -1.8 6.2 -2.8 Min - Max 1.0 - 12.0 -10.1 - 4.8 0.9 - 12.0 -10.5 - 1.0

CONFIDENTIAL

462

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.2 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.80 (0.20) -0.198 0.351 ( -0.62, 0.22)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -2.51 (0.27)

158 -3.10 (0.25) -0.596 0.030 ( -1.13, -0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.84 (0.29)

156 -3.83 (0.28) -0.991 0.001 ( -1.58, -0.40)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -3.21 (0.31)

153 -4.29 (0.29) -1.074 <0.001 ( -1.70, -0.44)

RM2008/00422/00

155 -1.60 (0.20)

CONFIDENTIAL

463

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.2 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -2.45 (0.24) -3.19 (0.23) LS Mean Difference -0.741 p-value vs. Placebo 0.004 95% C.I. ( -1.24, -0.24)

CONFIDENTIAL

464

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.3 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 8.7 (0.16) 8.9 (0.16) Median 8.8 9 Min - Max 3.5 - 12.0 2.0 - 12.0 155 -1.4 (0.18) -1 -10.2 - 3.8

160 7.2 (0.20) 7.3 1.1 - 12.0

160 -1.7 (0.16) -1.4 -8.0 - 2.2

Week 2 n Mean (Std Err) Median Min - Max

153 6.6 (0.23) 6.7 0.9 - 12.0

153 -2.1 (0.22) -1.4 -10.9 - 4.5

158 6.1 (0.24) 6.1 0.1 - 12.0

158 -2.8 (0.21) -2.4 -9.1 - 2.8

Week 3 n Mean (Std Err) Median Min - Max

151 6.2 (0.24) 6.4 0.0 - 12.0

151 -2.4 (0.24) -1.7 -11.2 - 4.8

156 5.6 (0.25) 5.4 0.0 - 12.0

156 -3.4 (0.23) -3.3 -10.7 - 2.9

Week 4 n Mean (Std Err) Median Min - Max

149 6.0 (0.25) 6.3 0.0 - 12.0

149 -2.7 (0.25) -1.9 -11.5 - 5.8

153 5.3 (0.26) 5.1 0.0 - 12.0

153 -3.7 (0.25) -3.6 -12.0 - 2.4

RM2008/00422/00

155 7.3 (0.21) 7.4 1.1 - 12.0

CONFIDENTIAL

465

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.3 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 6.6 (0.22) -2.1 (0.20) 6.0 (0.22) -2.8 (0.19) Median 6.6 -1.4 5.9 -2.6 Min - Max 0.8 - 12.0 -10.9 - 4.6 0.6 - 12.0 -9.0 - 1.6

CONFIDENTIAL

466

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.4 Analysis of Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.78 (0.21) -0.223 0.326 ( -0.67, 0.22)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -2.24 (0.28)

158 -2.87 (0.26) -0.631 0.028 ( -1.19, -0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.66 (0.30)

156 -3.50 (0.29) -0.836 0.008 ( -1.45, -0.22)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -2.96 (0.32)

153 -3.90 (0.30) -0.937 0.005 ( -1.60, -0.28)

RM2008/00422/00

155 -1.56 (0.22)

CONFIDENTIAL

467

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.4 Analysis of Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -2.29 (0.25) -2.97 (0.24) LS Mean Difference -0.685 p-value vs. Placebo 0.010 95% C.I. ( -1.20, -0.17)

CONFIDENTIAL

468

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.5 Summary of Daily Reflective Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 6.6 (0.11) 6.3 (0.12) Median 6.4 6.1 Min - Max 3.9 - 9.0 1.0 - 9.0 155 -1.3 (0.14) -0.9 -8.0 - 3.3

160 5.1 (0.14) 5.1 0.2 - 9.0

160 -1.2 (0.11) -0.9 -6.5 - 0.9

Week 2 n Mean (Std Err) Median Min - Max

153 4.7 (0.18) 4.6 0.0 - 9.0

153 -1.9 (0.17) -1.6 -9.0 - 2.9

158 4.4 (0.18) 4.3 0.0 - 9.0

158 -2.0 (0.16) -1.7 -6.9 - 2.0

Week 3 n Mean (Std Err) Median Min - Max

151 4.4 (0.20) 4.6 0.0 - 9.0

151 -2.1 (0.18) -1.8 -8.2 - 2.9

156 3.9 (0.19) 3.8 0.0 - 9.0

156 -2.4 (0.18) -2.1 -7.9 - 2.8

Week 4 n Mean (Std Err) Median Min - Max

149 4.1 (0.21) 4.4 0.0 - 9.0

149 -2.4 (0.20) -2 -8.6 - 2.8

153 3.6 (0.20) 3.4 0.0 - 9.0

153 -2.8 (0.19) -2.9 -9.0 - 1.9

RM2008/00422/00

155 5.3 (0.16) 5.4 0.1 - 9.0

CONFIDENTIAL

469

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.5 Summary of Daily Reflective Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 4.7 (0.18) -1.9 (0.16) 4.2 (0.16) -2.0 (0.15) Median 4.6 -1.6 4.2 -1.8 Min - Max 0.3 - 9.0 -8.4 - 2.6 0.2 - 9.0 -6.9 - 1.5

CONFIDENTIAL

470

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.6 Analysis of Mean Change from Baseline in Daily Reflective Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.29 (0.16) 0.072 0.671 ( -0.26, 0.41)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -2.01 (0.21)

158 -2.16 (0.20) -0.153 0.491 ( -0.59, 0.28)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.29 (0.24)

156 -2.64 (0.23) -0.357 0.147 ( -0.84, 0.13)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -2.53 (0.25)

153 -3.01 (0.24) -0.479 0.070 ( -1.00, 0.04)

RM2008/00422/00

155 -1.36 (0.16)

CONFIDENTIAL

471

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.6 Analysis of Mean Change from Baseline in Daily Reflective Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -1.99 (0.20) -2.23 (0.19) LS Mean Difference -0.240 p-value vs. Placebo 0.243 95% C.I. ( -0.64, 0.16)

CONFIDENTIAL

472

RM2008/00422/00

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Page 1 of 2 Table 7.7 Summary of AM Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 9.1 (0.14) 9.1 (0.14) Median 9.3 9 Min - Max 5.3 - 12.0 3.5 - 12.0 155 -1.4 (0.17) -1.1 -10.1 - 3.3

160 7.4 (0.19) 7.6 0.7 - 12.0

160 -1.7 (0.15) -1.5 -8.6 - 2.2

Week 2 n Mean (Std Err) Median Min - Max

153 6.8 (0.21) 7 0.7 - 12.0

153 -2.2 (0.20) -1.8 -10.9 - 3.1

158 6.2 (0.23) 6.2 0.3 - 12.0

158 -2.9 (0.21) -2.5 -11.4 - 1.9

Week 3 n Mean (Std Err) Median Min - Max

151 6.5 (0.23) 6.6 0.0 - 12.0

151 -2.6 (0.22) -2.4 -11.6 - 3.6

156 5.5 (0.24) 5.8 0.0 - 12.0

156 -3.6 (0.23) -3.3 -11.3 - 2.4

Week 4 n Mean (Std Err) Median Min - Max

149 6.2 (0.24) 6.7 0.0 - 12.0

149 -2.9 (0.24) -2.5 -10.4 - 4.5

153 5.3 (0.26) 5.4 0.0 - 12.0

153 -4.0 (0.25) -3.9 -12.0 - 2.0

RM2008/00422/00

155 7.7 (0.19) 7.9 1.9 - 12.0

CONFIDENTIAL

473

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.7 Summary of AM Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 6.9 (0.20) -2.2 (0.19) 6.1 (0.21) -3.0 (0.19) Median 7.1 -1.6 6.2 -2.7 Min - Max 0.9 - 12.0 -10.8 - 3.2 0.7 - 12.0 -10.6 - 1.3

CONFIDENTIAL

474

RM2008/00422/00

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Page 1 of 2

Table 7.8 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.74 (0.20) -0.202 0.351 ( -0.63, 0.22)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -2.43 (0.27)

158 -3.07 (0.26) -0.640 0.021 ( -1.18, -0.10)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.81 (0.29)

156 -3.81 (0.28) -1.004 <0.001 ( -1.60, -0.41)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -3.17 (0.31)

153 -4.21 (0.30) -1.048 0.001 ( -1.69, -0.41)

RM2008/00422/00

155 -1.54 (0.21)

CONFIDENTIAL

475

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.8 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -2.40 (0.24) -3.15 (0.23) LS Mean Difference -0.746 p-value vs. Placebo 0.003 95% C.I. ( -1.24, -0.25)

CONFIDENTIAL

476

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.9 Summary of PM Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 9.1 (0.13) 9.2 (0.14) Median 9 9 Min - Max 5.3 - 12.0 3.5 - 12.0 155 -1.5 (0.17) -1.2 -9.0 - 5.9

160 7.4 (0.19) 7.6 1.2 - 12.0

160 -1.8 (0.15) -1.6 -9.3 - 2.2

Week 2 n Mean (Std Err) Median Min - Max

153 6.8 (0.21) 6.9 0.0 - 12.0

153 -2.3 (0.21) -2 -11.4 - 6.3

158 6.3 (0.23) 6.3 0.3 - 12.0

158 -3.0 (0.21) -2.6 -11.4 - 3.5

Week 3 n Mean (Std Err) Median Min - Max

151 6.5 (0.23) 6.7 0.0 - 12.0

151 -2.6 (0.24) -2.2 -9.7 - 6.5

156 5.6 (0.24) 5.3 0.0 - 12.0

156 -3.6 (0.23) -3.4 -10.9 - 2.1

Week 4 n Mean (Std Err) Median Min - Max

148 6.2 (0.24) 6.5 0.0 - 12.0

148 -2.9 (0.25) -2.4 -10.8 - 6.8

153 5.2 (0.25) 5.4 0.0 - 12.0

153 -4.1 (0.25) -4 -12.0 - 2.2

RM2008/00422/00

155 7.6 (0.19) 7.6 2.0 - 12.0

CONFIDENTIAL

477

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.9 Summary of PM Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 6.8 (0.21) -2.3 (0.20) 6.1 (0.21) -3.1 (0.19) Median 7 -1.9 6.1 -3 Min - Max 1.1 - 12.0 -9.5 - 6.3 1.2 - 12.0 -10.4 - 1.5

CONFIDENTIAL

478

RM2008/00422/00

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Page 1 of 2

Table 7.10 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.90 (0.20) -0.208 0.346 ( -0.64, 0.23)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -2.60 (0.27)

158 -3.15 (0.26) -0.553 0.051 ( -1.11, 0.00)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.87 (0.30)

156 -3.87 (0.29) -0.999 0.001 ( -1.61, -0.39)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -3.27 (0.31)

153 -4.36 (0.30) -1.098 <0.001 ( -1.74, -0.46)

RM2008/00422/00

155 -1.70 (0.21)

CONFIDENTIAL

479

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.10 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -2.51 (0.25) -3.26 (0.24) LS Mean Difference -0.758 p-value vs. Placebo 0.004 95% C.I. ( -1.27, -0.25)

CONFIDENTIAL

480

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.11 Summary of Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 9.1 (0.13) 9.1 (0.14) Median 9 8.9 Min - Max 6.0 - 12.0 3.5 - 12.0 155 -16.2 (1.75) -11.8 -79.8 - 61.3

160 7.4 (0.18) 7.5 0.9 - 12.0

160 -18.9 (1.60) -17.9 -79.6 - 28.0

Week 2 n Mean (Std Err) Median Min - Max

153 6.8 (0.21) 6.9 0.4 - 12.0

153 -24.8 (2.18) -21.1 -95.7 - 73.7

158 6.3 (0.22) 6.3 0.4 - 12.0

158 -32.3 (2.18) -30.8 -95.8 - 33.3

Week 3 n Mean (Std Err) Median Min - Max

151 6.5 (0.23) 6.7 0.0 - 12.0

151 -28.2 (2.42) -25.1 -100 - 79.3

156 5.6 (0.24) 5.5 0.0 - 12.0

156 -39.6 (2.42) -36.8 -100 - 33.7

Week 4 n Mean (Std Err) Median Min - Max

149 6.2 (0.24) 6.3 0.0 - 12.0

149 -31.3 (2.56) -26.4 -100 - 88.2

153 5.2 (0.25) 5.4 0.0 - 12.0

153 -43.8 (2.59) -42.9 -100 - 30.8

RM2008/00422/00

155 7.6 (0.19) 7.9 2.1 - 12.0

CONFIDENTIAL

481

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.11 Summary of Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 6.9 (0.20) -24.4 (2.05) 6.1 (0.21) -33.3 (2.00) Median 7 -20 6.2 -32.7 Min - Max 1.0 - 12.0 -88.3 - 75.2 0.9 - 12.0 -88.7 - 12.6

CONFIDENTIAL

482

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Table 7.12 Analysis of Mean Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -19.45 (2.18) -2.354 0.318 ( -6.99, 2.28)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -26.67 (2.93)

158 -33.99 (2.79) -7.319 0.016 (-13.24, -1.40)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -30.58 (3.23)

156 -42.19 (3.08) -11.613 <0.001 (-18.18, -5.04)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -34.56 (3.40)

153 -46.95 (3.23) -12.386 <0.001 (-19.32, -5.45)

RM2008/00422/00

155 -17.09 (2.27)

CONFIDENTIAL

483

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.12 Analysis of Mean Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -26.39 (2.69) -35.03 (2.59) LS Mean Difference -8.642 p-value vs. Placebo 0.002 95% C.I. (-14.14, -3.15)

CONFIDENTIAL

484

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.13 Summary of Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 8.7 (0.16) 8.9 (0.16) Median 8.8 9 Min - Max 3.5 - 12.0 2.0 - 12.0 155 -16.0 (1.93) -10.7 -87.6 - 60.0

160 7.2 (0.20) 7.3 1.1 - 12.0

160 -19.3 (1.75) -18.1 -80.1 - 34.1

Week 2 n Mean (Std Err) Median Min - Max

153 6.6 (0.23) 6.7 0.9 - 12.0

153 -22.8 (2.36) -17.9 -92.7 - 71.4

158 6.1 (0.24) 6.1 0.1 - 12.0

158 -31.5 (2.38) -29 -98.1 - 47.8

Week 3 n Mean (Std Err) Median Min - Max

151 6.2 (0.24) 6.4 0.0 - 12.0

151 -27.4 (2.62) -21.4 -100 - 76.0

156 5.6 (0.25) 5.4 0.0 - 12.0

156 -37.6 (2.56) -37.5 -100 - 47.6

Week 4 n Mean (Std Err) Median Min - Max

149 6.0 (0.25) 6.3 0.0 - 12.0

149 -29.8 (2.77) -26.2 -100 - 92.0

153 5.3 (0.26) 5.1 0.0 - 12.0

153 -41.8 (2.74) -39.8 -100 - 41.6

RM2008/00422/00

155 7.3 (0.21) 7.4 1.1 - 12.0

CONFIDENTIAL

485

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.13 Summary of Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 6.6 (0.22) -23.3 (2.21) 6.0 (0.22) -32.1 (2.14) Median 6.6 -17.9 5.9 -29.7 Min - Max 0.8 - 12.0 -93.0 - 74.2 0.6 - 12.0 -88.8 - 27.8

CONFIDENTIAL

486

RM2008/00422/00

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Page 1 of 2

Table 7.14 Analysis of Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -19.55 (2.38) -2.878 0.266 ( -7.96, 2.20)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -23.91 (3.17)

158 -32.44 (3.02) -8.530 0.010 (-14.99, -2.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -28.84 (3.45)

156 -39.28 (3.29) -10.449 0.004 (-17.50, -3.40)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -32.43 (3.63)

153 -44.39 (3.45) -11.968 0.002 (-19.44, -4.50)

RM2008/00422/00

155 -16.67 (2.48)

CONFIDENTIAL

487

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.14 Analysis of Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -24.87 (2.89) -33.52 (2.77) LS Mean Difference -8.645 p-value vs. Placebo 0.004 95% C.I. (-14.56, -2.73)

CONFIDENTIAL

488

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.15 Summary of Daily Reflective Symptoms Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.3 (0.04) 2.3 (0.04) Median 2.3 2.3 Min - Max 0.8 - 3.0 0.0 - 3.0 155 -0.4 (0.04) -0.2 -2.5 - 1.1

160 1.9 (0.05) 2 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.4 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.8 (0.06) 1.9 0.0 - 3.0

153 -0.6 (0.06) -0.5 -2.9 - 1.1

158 1.6 (0.06) 1.8 0.0 - 3.0

158 -0.7 (0.05) -0.7 -3.0 - 0.8

Week 3 n Mean (Std Err) Median Min - Max

151 1.7 (0.07) 1.7 0.0 - 3.0

151 -0.7 (0.06) -0.6 -2.4 - 1.1

156 1.5 (0.07) 1.6 0.0 - 3.0

156 -0.9 (0.06) -0.8 -2.9 - 1.4

Week 4 n Mean (Std Err) Median Min - Max

149 1.6 (0.07) 1.6 0.0 - 3.0

149 -0.7 (0.07) -0.7 -2.6 - 1.1

153 1.4 (0.07) 1.4 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 1.5

RM2008/00422/00

155 2.0 (0.05) 2 0.0 - 3.0

CONFIDENTIAL

489

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.15 Summary of Daily Reflective Symptoms Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.8 (0.06) -0.6 (0.05) 1.6 (0.06) -0.7 (0.05) Median 1.8 -0.5 1.7 -0.7 Min - Max 0.0 - 3.0 -2.6 - 1.1 0.0 - 3.0 -2.8 - 0.9

CONFIDENTIAL

490

RM2008/00422/00

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Page 1 of 2

Table 7.16 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.39 (0.05) -0.041 0.479 ( -0.15, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.56 (0.07)

158 -0.69 (0.07) -0.122 0.101 ( -0.27, 0.02)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.67 (0.08)

156 -0.88 (0.08) -0.204 0.015 ( -0.37, -0.04)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.77 (0.09)

153 -1.01 (0.08) -0.240 0.008 ( -0.42, -0.06)

RM2008/00422/00

155 -0.35 (0.06)

CONFIDENTIAL

491

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.16 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.57 (0.07) -0.73 (0.06) LS Mean Difference -0.162 p-value vs. Placebo 0.019 95% C.I. ( -0.30, -0.03)

CONFIDENTIAL

492

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.17 Summary of Daily Reflective Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.6 (0.03) 2.6 (0.03) Median 2.6 2.6 Min - Max 1.8 - 3.0 1.4 - 3.0 155 -0.4 (0.04) -0.3 -2.4 - 0.4

160 2.1 (0.05) 2.1 0.7 - 3.0

160 -0.4 (0.04) -0.4 -1.9 - 0.5

Week 2 n Mean (Std Err) Median Min - Max

153 2.0 (0.05) 2.1 0.1 - 3.0

153 -0.6 (0.05) -0.5 -2.9 - 0.7

158 1.8 (0.06) 1.9 0.1 - 3.0

158 -0.7 (0.05) -0.7 -2.6 - 0.7

Week 3 n Mean (Std Err) Median Min - Max

151 1.9 (0.06) 2 0.0 - 3.0

151 -0.7 (0.06) -0.5 -2.6 - 0.8

156 1.7 (0.06) 1.8 0.0 - 3.0

156 -0.9 (0.06) -0.8 -2.6 - 0.9

Week 4 n Mean (Std Err) Median Min - Max

149 1.9 (0.06) 2 0.0 - 3.0

149 -0.7 (0.06) -0.6 -2.9 - 0.8

153 1.6 (0.07) 1.8 0.0 - 3.0

153 -1.0 (0.06) -0.9 -3.0 - 0.9

RM2008/00422/00

155 2.2 (0.04) 2.2 0.6 - 3.0

CONFIDENTIAL

493

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.17 Summary of Daily Reflective Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 2.0 (0.05) -0.6 (0.05) 1.8 (0.05) -0.7 (0.05) Median 2.1 -0.5 1.9 -0.7 Min - Max 0.3 - 3.0 -2.7 - 0.6 0.3 - 3.0 -2.4 - 0.5

CONFIDENTIAL

494

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.18 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.47 (0.05) -0.047 0.391 ( -0.15, 0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.64 (0.07)

158 -0.79 (0.07) -0.147 0.043 ( -0.29, -0.00)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.72 (0.08)

156 -0.95 (0.07) -0.230 0.004 ( -0.38, -0.08)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.81 (0.08)

153 -1.05 (0.08) -0.239 0.006 ( -0.41, -0.07)

RM2008/00422/00

155 -0.42 (0.05)

CONFIDENTIAL

495

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.18 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.63 (0.06) -0.80 (0.06) LS Mean Difference -0.173 p-value vs. Placebo 0.009 95% C.I. ( -0.30, -0.04)

CONFIDENTIAL

496

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.19 Summary of Daily Reflective Symptoms Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.05) 2.2 (0.04) Median 2.3 2.1 Min - Max 0.0 - 3.0 0.4 - 3.0 155 -0.4 (0.05) -0.3 -2.2 - 1.4

160 1.8 (0.05) 1.9 0.1 - 3.0

160 -0.4 (0.04) -0.4 -2.6 - 0.6

Week 2 n Mean (Std Err) Median Min - Max

153 1.6 (0.06) 1.7 0.0 - 3.0

153 -0.6 (0.06) -0.4 -2.8 - 1.6

158 1.5 (0.06) 1.5 0.0 - 3.0

158 -0.7 (0.06) -0.7 -2.9 - 0.8

Week 3 n Mean (Std Err) Median Min - Max

151 1.6 (0.07) 1.6 0.0 - 3.0

151 -0.7 (0.06) -0.6 -2.8 - 1.6

156 1.3 (0.07) 1.3 0.0 - 3.0

156 -0.9 (0.06) -0.9 -3.0 - 0.7

Week 4 n Mean (Std Err) Median Min - Max

149 1.5 (0.07) 1.5 0.0 - 3.0

149 -0.7 (0.07) -0.6 -2.8 - 1.9

153 1.2 (0.07) 1.2 0.0 - 3.0

153 -1.1 (0.06) -1 -3.0 - 0.5

RM2008/00422/00

155 1.9 (0.06) 1.9 0.0 - 3.0

CONFIDENTIAL

497

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.19 Summary of Daily Reflective Symptoms Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.6 (0.05) 1.5 (0.06) -0.8 (0.05) Median 1.7 -0.5 1.5 -0.7 Min - Max 0.0 - 3.0 -2.6 - 1.6 0.1 - 3.0 -2.8 - 0.5

CONFIDENTIAL

498

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.20 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.47 (0.06) -0.049 0.421 ( -0.17, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.65 (0.07)

158 -0.80 (0.07) -0.147 0.054 ( -0.30, 0.00)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.73 (0.08)

156 -1.00 (0.08) -0.260 0.002 ( -0.42, -0.10)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.80 (0.08)

153 -1.11 (0.08) -0.313 <0.001 ( -0.48, -0.14)

RM2008/00422/00

155 -0.42 (0.06)

CONFIDENTIAL

499

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.20 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.63 (0.07) -0.82 (0.06) LS Mean Difference -0.193 p-value vs. Placebo 0.006 95% C.I. ( -0.33, -0.06)

CONFIDENTIAL

500

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.21 Summary of Daily Reflective Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.0 (0.05) 2.0 (0.05) Median 2 2 Min - Max 0.0 - 3.0 0.1 - 3.0 155 -0.4 (0.05) -0.3 -2.4 - 1.2

160 1.6 (0.06) 1.5 0.0 - 3.0

160 -0.4 (0.04) -0.4 -2.5 - 1.5

Week 2 n Mean (Std Err) Median Min - Max

153 1.4 (0.06) 1.3 0.0 - 3.0

153 -0.6 (0.06) -0.5 -2.9 - 1.7

158 1.3 (0.06) 1.1 0.0 - 3.0

158 -0.8 (0.06) -0.7 -2.9 - 0.7

Week 3 n Mean (Std Err) Median Min - Max

151 1.3 (0.06) 1.2 0.0 - 3.0

151 -0.6 (0.06) -0.6 -2.6 - 2.1

156 1.1 (0.07) 1 0.0 - 3.0

156 -0.9 (0.07) -0.8 -3.0 - 0.7

Week 4 n Mean (Std Err) Median Min - Max

149 1.2 (0.07) 1.1 0.0 - 3.0

149 -0.7 (0.07) -0.7 -2.6 - 2.4

153 1.0 (0.07) 1 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 0.6

RM2008/00422/00

155 1.6 (0.06) 1.6 0.0 - 3.0

CONFIDENTIAL

501

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.21 Summary of Daily Reflective Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.4 (0.06) -0.5 (0.05) 1.2 (0.06) -0.8 (0.05) Median 1.3 -0.5 1.1 -0.8 Min - Max 0.0 - 3.0 -2.5 - 1.8 0.0 - 3.0 -2.8 - 0.4

CONFIDENTIAL

502

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.22 Analysis of Mean Change from Baseline in Daily Reflective Symptoms Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.47 (0.06) -0.058 0.345 ( -0.18, 0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.66 (0.07)

158 -0.83 (0.07) -0.171 0.024 ( -0.32, -0.02)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.71 (0.08)

156 -1.00 (0.08) -0.289 <0.001 ( -0.45, -0.13)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.83 (0.08)

153 -1.10 (0.08) -0.276 0.001 ( -0.44, -0.11)

RM2008/00422/00

155 -0.42 (0.06)

CONFIDENTIAL

503

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.22 Analysis of Mean Change from Baseline in Daily Reflective Symptoms Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.63 (0.07) -0.84 (0.06) LS Mean Difference -0.207 p-value vs. Placebo 0.003 95% C.I. ( -0.34, -0.07)

CONFIDENTIAL

504

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.23 Summary of AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.05) 2.3 (0.05) Median 2.3 2.3 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.3 (0.05) -0.3 -2.9 - 1.2

160 1.9 (0.06) 2 0.0 - 3.0

160 -0.4 (0.05) -0.3 -2.3 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.7 (0.07) 1.9 0.0 - 3.0

153 -0.5 (0.06) -0.3 -3.0 - 1.3

158 1.6 (0.07) 1.7 0.0 - 3.0

158 -0.7 (0.06) -0.6 -2.6 - 0.8

Week 3 n Mean (Std Err) Median Min - Max

151 1.6 (0.07) 1.7 0.0 - 3.0

151 -0.6 (0.07) -0.4 -3.0 - 1.3

156 1.5 (0.07) 1.6 0.0 - 3.0

156 -0.8 (0.07) -0.8 -2.7 - 1.9

Week 4 n Mean (Std Err) Median Min - Max

149 1.6 (0.07) 1.7 0.0 - 3.0

149 -0.7 (0.07) -0.5 -3.0 - 1.3

153 1.4 (0.08) 1.4 0.0 - 3.0

153 -0.9 (0.07) -1 -3.0 - 1.8

RM2008/00422/00

155 1.9 (0.06) 2 0.0 - 3.0

CONFIDENTIAL

505

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.23 Summary of AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.5 (0.06) 1.6 (0.06) -0.7 (0.06) Median 1.8 -0.3 1.6 -0.6 Min - Max 0.0 - 3.0 -2.9 - 1.2 0.0 - 3.0 -2.5 - 1.2

CONFIDENTIAL

506

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.24 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.39 (0.06) -0.061 0.369 ( -0.19, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.50 (0.08)

158 -0.65 (0.08) -0.149 0.069 ( -0.31, 0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.62 (0.09)

156 -0.79 (0.08) -0.168 0.060 ( -0.34, 0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.69 (0.09)

153 -0.91 (0.09) -0.217 0.025 ( -0.41, -0.03)

RM2008/00422/00

155 -0.33 (0.07)

CONFIDENTIAL

507

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.24 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.52 (0.07) -0.68 (0.07) LS Mean Difference -0.161 p-value vs. Placebo 0.033 95% C.I. ( -0.31, -0.01)

CONFIDENTIAL

508

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.25 Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.6 (0.03) 2.6 (0.03) Median 2.5 2.7 Min - Max 1.0 - 3.0 1.3 - 3.0 155 -0.3 (0.04) -0.3 -2.1 - 1.0

160 2.1 (0.05) 2.1 0.7 - 3.0

160 -0.4 (0.04) -0.3 -2.3 - 0.5

Week 2 n Mean (Std Err) Median Min - Max

153 2.1 (0.05) 2.1 0.1 - 3.0

153 -0.5 (0.05) -0.3 -2.7 - 1.0

158 1.9 (0.06) 2 0.1 - 3.0

158 -0.6 (0.05) -0.5 -2.4 - 0.8

Week 3 n Mean (Std Err) Median Min - Max

151 2.0 (0.06) 2 0.0 - 3.0

151 -0.5 (0.06) -0.4 -2.6 - 1.0

156 1.8 (0.06) 2 0.0 - 3.0

156 -0.8 (0.06) -0.8 -2.7 - 1.0

Week 4 n Mean (Std Err) Median Min - Max

149 1.9 (0.06) 2 0.0 - 3.0

149 -0.6 (0.06) -0.5 -3.0 - 1.0

153 1.7 (0.07) 1.8 0.0 - 3.0

153 -0.9 (0.07) -0.8 -3.0 - 0.8

RM2008/00422/00

155 2.3 (0.05) 2.3 0.9 - 3.0

CONFIDENTIAL

509

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.25 Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 2.1 (0.05) -0.5 (0.05) 1.9 (0.05) -0.7 (0.05) Median 2.1 -0.4 2 -0.6 Min - Max 0.4 - 3.0 -2.6 - 1.0 0.4 - 3.0 -2.3 - 0.7

CONFIDENTIAL

510

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.26 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.42 (0.05) -0.108 0.050 ( -0.22, -0.00)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.51 (0.07)

158 -0.68 (0.07) -0.166 0.025 ( -0.31, -0.02)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.61 (0.08)

156 -0.83 (0.07) -0.228 0.005 ( -0.39, -0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.68 (0.08)

153 -0.93 (0.08) -0.250 0.004 ( -0.42, -0.08)

RM2008/00422/00

155 -0.31 (0.05)

CONFIDENTIAL

511

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.26 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.51 (0.06) -0.71 (0.06) LS Mean Difference -0.194 p-value vs. Placebo 0.004 95% C.I. ( -0.32, -0.06)

CONFIDENTIAL

512

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.27 Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.05) 2.2 (0.05) Median 2.3 2.3 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.7 - 1.7

160 1.8 (0.06) 1.9 0.1 - 3.0

160 -0.4 (0.05) -0.4 -2.3 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.6 (0.07) 1.7 0.0 - 3.0

153 -0.6 (0.06) -0.4 -2.8 - 1.4

158 1.5 (0.07) 1.6 0.0 - 3.0

158 -0.7 (0.06) -0.6 -2.7 - 0.9

Week 3 n Mean (Std Err) Median Min - Max

151 1.5 (0.07) 1.5 0.0 - 3.0

151 -0.7 (0.07) -0.6 -3.0 - 1.6

156 1.3 (0.07) 1.3 0.0 - 3.0

156 -0.9 (0.06) -0.9 -3.0 - 1.0

Week 4 n Mean (Std Err) Median Min - Max

149 1.5 (0.08) 1.4 0.0 - 3.0

149 -0.7 (0.07) -0.5 -3.0 - 2.0

153 1.3 (0.07) 1.1 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 1.0

RM2008/00422/00

155 1.8 (0.06) 1.9 0.0 - 3.0

CONFIDENTIAL

513

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.27 Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.6 (0.07) -0.6 (0.06) 1.5 (0.06) -0.7 (0.05) Median 1.6 -0.5 1.5 -0.7 Min - Max 0.0 - 3.0 -2.9 - 1.7 0.1 - 3.0 -2.7 - 0.8

CONFIDENTIAL

514

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.28 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.50 (0.06) -0.002 0.980 ( -0.13, 0.13)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.65 (0.08)

158 -0.78 (0.07) -0.135 0.096 ( -0.29, 0.02)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.75 (0.08)

156 -0.96 (0.08) -0.207 0.018 ( -0.38, -0.04)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.84 (0.09)

153 -1.08 (0.09) -0.237 0.012 ( -0.42, -0.05)

RM2008/00422/00

155 -0.49 (0.06)

CONFIDENTIAL

515

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.28 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.66 (0.07) -0.81 (0.07) LS Mean Difference -0.149 p-value vs. Placebo 0.046 95% C.I. ( -0.30, -0.00)

CONFIDENTIAL

516

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.29 Summary of AM Pre-Dose Instantaneous Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 1.7 (0.07) 1.8 (0.06) Median 2 2 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.2 -2.8 - 0.8

160 1.4 (0.07) 1.3 0.0 - 3.0

160 -0.5 (0.05) -0.4 -2.7 - 1.1

Week 2 n Mean (Std Err) Median Min - Max

153 1.2 (0.07) 1.1 0.0 - 3.0

153 -0.5 (0.06) -0.4 -3.0 - 1.5

158 1.1 (0.07) 1 0.0 - 3.0

158 -0.7 (0.06) -0.7 -2.8 - 1.5

Week 3 n Mean (Std Err) Median Min - Max

151 1.1 (0.07) 1 0.0 - 3.0

151 -0.6 (0.07) -0.5 -3.0 - 1.7

156 0.9 (0.07) 0.9 0.0 - 3.0

156 -0.9 (0.07) -0.8 -3.0 - 1.4

Week 4 n Mean (Std Err) Median Min - Max

149 1.0 (0.07) 1 0.0 - 3.0

149 -0.7 (0.07) -0.5 -3.0 - 2.3

153 0.9 (0.07) 0.9 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 1.4

RM2008/00422/00

155 1.3 (0.07) 1.3 0.0 - 3.0

CONFIDENTIAL

517

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.29 Summary of AM Pre-Dose Instantaneous Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.2 (0.07) -0.5 (0.06) 1.1 (0.06) -0.7 (0.06) Median 1.1 -0.4 1 -0.7 Min - Max 0.0 - 3.0 -2.9 - 1.5 0.0 - 3.0 -2.9 - 1.1

CONFIDENTIAL

518

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.30 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.48 (0.06) -0.042 0.535 ( -0.18, 0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.59 (0.08)

158 -0.76 (0.07) -0.167 0.035 ( -0.32, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.69 (0.08)

156 -0.92 (0.08) -0.225 0.009 ( -0.39, -0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.76 (0.09)

153 -0.98 (0.08) -0.223 0.014 ( -0.40, -0.05)

RM2008/00422/00

155 -0.44 (0.07)

CONFIDENTIAL

519

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.30 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.60 (0.07) -0.77 (0.07) LS Mean Difference -0.172 p-value vs. Placebo 0.018 95% C.I. ( -0.31, -0.03)

CONFIDENTIAL

520

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.31 Summary of AM Reflective Symptom Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.3 (0.04) 2.3 (0.04) Median 2.3 2.3 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.6 - 0.7

160 1.9 (0.05) 2 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.4 - 1.0

Week 2 n Mean (Std Err) Median Min - Max

153 1.8 (0.06) 2 0.0 - 3.0

153 -0.5 (0.06) -0.5 -2.9 - 1.0

158 1.6 (0.06) 1.7 0.0 - 3.0

158 -0.7 (0.05) -0.7 -3.0 - 1.0

Week 3 n Mean (Std Err) Median Min - Max

151 1.7 (0.07) 1.8 0.0 - 3.0

151 -0.6 (0.06) -0.5 -2.9 - 1.0

156 1.4 (0.07) 1.5 0.0 - 3.0

156 -0.9 (0.06) -0.8 -3.0 - 1.4

Week 4 n Mean (Std Err) Median Min - Max

149 1.6 (0.07) 1.6 0.0 - 3.0

149 -0.7 (0.07) -0.6 -2.6 - 1.3

153 1.4 (0.07) 1.4 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 1.3

RM2008/00422/00

155 2.0 (0.05) 2 0.0 - 3.0

CONFIDENTIAL

521

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.31 Summary of AM Reflective Symptom Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.8 (0.06) -0.5 (0.05) 1.6 (0.06) -0.7 (0.05) Median 1.9 -0.4 1.6 -0.6 Min - Max 0.0 - 3.0 -2.7 - 0.7 0.0 - 3.0 -2.8 - 1.0

CONFIDENTIAL

522

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.32 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.41 (0.06) -0.036 0.552 ( -0.15, 0.08)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.57 (0.07)

158 -0.70 (0.07) -0.129 0.091 ( -0.28, 0.02)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.68 (0.08)

156 -0.91 (0.08) -0.231 0.007 ( -0.40, -0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.79 (0.09)

153 -1.02 (0.08) -0.238 0.010 ( -0.42, -0.06)

RM2008/00422/00

155 -0.38 (0.06)

CONFIDENTIAL

523

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.32 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.58 (0.07) -0.75 (0.06) LS Mean Difference -0.168 p-value vs. Placebo 0.016 95% C.I. ( -0.30, -0.03)

CONFIDENTIAL

524

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.33 Summary of AM Reflective Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.6 (0.03) 2.6 (0.03) Median 2.8 2.8 Min - Max 1.8 - 3.0 1.5 - 3.0 155 -0.4 (0.04) -0.2 -2.4 - 0.8

160 2.2 (0.05) 2 0.7 - 3.0

160 -0.4 (0.04) -0.3 -1.9 - 0.6

Week 2 n Mean (Std Err) Median Min - Max

153 2.1 (0.05) 2.1 0.0 - 3.0

153 -0.6 (0.05) -0.4 -2.7 - 0.7

158 1.9 (0.06) 2 0.1 - 3.0

158 -0.7 (0.06) -0.6 -2.8 - 0.6

Week 3 n Mean (Std Err) Median Min - Max

151 2.0 (0.06) 2 0.0 - 3.0

151 -0.7 (0.06) -0.6 -2.9 - 1.0

156 1.7 (0.06) 1.8 0.0 - 3.0

156 -0.9 (0.06) -0.9 -2.7 - 1.0

Week 4 n Mean (Std Err) Median Min - Max

149 1.9 (0.07) 2 0.0 - 3.0

149 -0.7 (0.06) -0.6 -3.0 - 0.8

153 1.6 (0.07) 1.8 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 1.0

RM2008/00422/00

155 2.3 (0.05) 2.3 0.4 - 3.0

CONFIDENTIAL

525

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.33 Summary of AM Reflective Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 2.1 (0.05) -0.6 (0.05) 1.8 (0.05) -0.7 (0.05) Median 2.1 -0.5 2 -0.7 Min - Max 0.3 - 3.0 -2.8 - 0.6 0.3 - 3.0 -2.5 - 0.6

CONFIDENTIAL

526

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.34 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.44 (0.05) -0.061 0.289 ( -0.17, 0.05)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.61 (0.07)

158 -0.79 (0.07) -0.183 0.015 ( -0.33, -0.04)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.71 (0.08)

156 -0.96 (0.07) -0.253 0.002 ( -0.41, -0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.80 (0.09)

153 -1.04 (0.08) -0.246 0.006 ( -0.42, -0.07)

RM2008/00422/00

155 -0.38 (0.05)

CONFIDENTIAL

527

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.34 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.61 (0.06) -0.80 (0.06) LS Mean Difference -0.193 p-value vs. Placebo 0.004 95% C.I. ( -0.33, -0.06)

CONFIDENTIAL

528

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.35 Summary of AM Reflective Symptom Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.05) 2.2 (0.05) Median 2.3 2.3 Min - Max 0.0 - 3.0 0.3 - 3.0 155 -0.4 (0.05) -0.3 -2.4 - 1.3

160 1.8 (0.05) 1.9 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.6 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.6 (0.06) 1.7 0.0 - 3.0

153 -0.6 (0.06) -0.4 -2.6 - 1.0

158 1.5 (0.06) 1.5 0.0 - 3.0

158 -0.7 (0.06) -0.7 -2.8 - 0.8

Week 3 n Mean (Std Err) Median Min - Max

151 1.5 (0.07) 1.7 0.0 - 3.0

151 -0.7 (0.06) -0.6 -3.0 - 1.1

156 1.3 (0.07) 1.3 0.0 - 3.0

156 -0.9 (0.06) -0.9 -3.0 - 0.5

Week 4 n Mean (Std Err) Median Min - Max

149 1.5 (0.07) 1.7 0.0 - 3.0

149 -0.7 (0.07) -0.6 -3.0 - 1.5

153 1.2 (0.07) 1.2 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 0.5

RM2008/00422/00

155 1.9 (0.06) 2 0.0 - 3.0

CONFIDENTIAL

529

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.35 Summary of AM Reflective Symptom Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.6 (0.05) 1.5 (0.06) -0.7 (0.05) Median 1.7 -0.5 1.6 -0.7 Min - Max 0.0 - 3.0 -2.6 - 1.1 0.0 - 3.0 -2.9 - 0.8

CONFIDENTIAL

530

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.36 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.45 (0.06) -0.050 0.415 ( -0.17, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.63 (0.07)

158 -0.78 (0.07) -0.154 0.044 ( -0.30, -0.00)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.74 (0.08)

156 -0.97 (0.08) -0.234 0.005 ( -0.40, -0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.79 (0.09)

153 -1.08 (0.08) -0.295 <0.001 ( -0.47, -0.12)

RM2008/00422/00

155 -0.40 (0.06)

CONFIDENTIAL

531

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.36 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.62 (0.07) -0.80 (0.06) LS Mean Difference -0.183 p-value vs. Placebo 0.009 95% C.I. ( -0.32, -0.05)

CONFIDENTIAL

532

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.37 Summary of AM Reflective Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 1.9 (0.05) 2.0 (0.06) Median 2 2 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.3 (0.05) -0.3 -2.7 - 1.5

160 1.6 (0.06) 1.5 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.4 - 1.2

Week 2 n Mean (Std Err) Median Min - Max

153 1.4 (0.06) 1.3 0.0 - 3.0

153 -0.6 (0.06) -0.4 -3.0 - 1.4

158 1.2 (0.06) 1.1 0.0 - 3.0

158 -0.8 (0.06) -0.8 -3.0 - 0.8

Week 3 n Mean (Std Err) Median Min - Max

151 1.3 (0.07) 1.3 0.0 - 3.0

151 -0.6 (0.06) -0.6 -2.9 - 1.8

156 1.1 (0.07) 1 0.0 - 3.0

156 -0.9 (0.07) -0.9 -3.0 - 0.8

Week 4 n Mean (Std Err) Median Min - Max

149 1.2 (0.07) 1 0.0 - 3.0

149 -0.7 (0.07) -0.8 -2.6 - 2.3

153 1.0 (0.07) 1 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 0.8

RM2008/00422/00

155 1.6 (0.06) 1.6 0.0 - 3.0

CONFIDENTIAL

533

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.37 Summary of AM Reflective Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.4 (0.06) -0.5 (0.05) 1.2 (0.06) -0.8 (0.06) Median 1.3 -0.4 1.1 -0.8 Min - Max 0.0 - 3.0 -2.7 - 1.5 0.0 - 3.0 -2.9 - 0.5

CONFIDENTIAL

534

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.38 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.45 (0.06) -0.057 0.375 ( -0.18, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.64 (0.07)

158 -0.81 (0.07) -0.167 0.032 ( -0.32, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.70 (0.08)

156 -0.97 (0.08) -0.277 0.001 ( -0.44, -0.11)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.80 (0.08)

153 -1.06 (0.08) -0.261 0.003 ( -0.43, -0.09)

RM2008/00422/00

155 -0.39 (0.06)

CONFIDENTIAL

535

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.38 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.61 (0.07) -0.81 (0.06) LS Mean Difference -0.199 p-value vs. Placebo 0.005 95% C.I. ( -0.34, -0.06)

CONFIDENTIAL

536

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.39 Summary of PM Reflective Symptom Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.3 (0.04) 2.3 (0.04) Median 2.3 2.3 Min - Max 1.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.4 - 1.5

160 1.9 (0.05) 2 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.4 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.8 (0.06) 1.9 0.0 - 3.0

153 -0.6 (0.06) -0.4 -2.9 - 1.5

158 1.6 (0.06) 1.7 0.0 - 3.0

158 -0.7 (0.06) -0.6 -3.0 - 0.9

Week 3 n Mean (Std Err) Median Min - Max

151 1.7 (0.07) 1.8 0.0 - 3.0

151 -0.7 (0.07) -0.6 -2.4 - 1.5

156 1.5 (0.07) 1.6 0.0 - 3.0

156 -0.8 (0.06) -0.8 -2.7 - 1.5

Week 4 n Mean (Std Err) Median Min - Max

148 1.6 (0.07) 1.7 0.0 - 3.0

148 -0.7 (0.07) -0.7 -3.0 - 1.5

153 1.4 (0.07) 1.3 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 1.8

RM2008/00422/00

155 2.0 (0.06) 2 0.0 - 3.0

CONFIDENTIAL

537

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.39 Summary of PM Reflective Symptom Scores for Rhinorrhea

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.8 (0.06) -0.6 (0.06) 1.6 (0.06) -0.7 (0.05) Median 1.9 -0.5 1.7 -0.7 Min - Max 0.1 - 3.0 -2.5 - 1.5 0.0 - 3.0 -2.7 - 1.0

CONFIDENTIAL

538

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.40 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.40 (0.06) -0.050 0.426 ( -0.17, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.57 (0.08)

158 -0.69 (0.07) -0.117 0.135 ( -0.27, 0.04)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.69 (0.08)

156 -0.87 (0.08) -0.182 0.037 ( -0.35, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -0.77 (0.09)

153 -1.02 (0.09) -0.249 0.008 ( -0.43, -0.06)

RM2008/00422/00

155 -0.35 (0.06)

CONFIDENTIAL

539

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.40 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Rhinorrhea ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.57 (0.07) -0.73 (0.07) LS Mean Difference -0.162 p-value vs. Placebo 0.024 95% C.I. ( -0.30, -0.02)

CONFIDENTIAL

540

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.41 Summary of PM Reflective Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.6 (0.03) 2.5 (0.03) Median 2.5 2.5 Min - Max 1.5 - 3.0 1.3 - 3.0 155 -0.4 (0.05) -0.3 -2.4 - 0.9

160 2.1 (0.05) 2 0.7 - 3.0

160 -0.5 (0.04) -0.4 -2.0 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.9 (0.06) 2 0.0 - 3.0

153 -0.6 (0.06) -0.5 -3.0 - 0.8

158 1.8 (0.06) 1.9 0.0 - 3.0

158 -0.7 (0.06) -0.7 -2.6 - 1.0

Week 3 n Mean (Std Err) Median Min - Max

151 1.9 (0.06) 2 0.0 - 3.0

151 -0.7 (0.06) -0.5 -2.5 - 0.9

156 1.7 (0.06) 1.7 0.0 - 3.0

156 -0.9 (0.06) -0.8 -2.7 - 1.0

Week 4 n Mean (Std Err) Median Min - Max

148 1.8 (0.06) 2 0.0 - 3.0

148 -0.7 (0.07) -0.6 -2.8 - 1.0

153 1.6 (0.07) 1.7 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 1.0

RM2008/00422/00

155 2.1 (0.05) 2.1 0.6 - 3.0

CONFIDENTIAL

541

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.41 Summary of PM Reflective Symptom Scores for Nasal Congestion

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 2.0 (0.05) -0.6 (0.05) 1.8 (0.05) -0.7 (0.05) Median 2 -0.5 1.9 -0.7 Min - Max 0.4 - 3.0 -2.6 - 0.5 0.3 - 3.0 -2.3 - 0.8

CONFIDENTIAL

542

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.42 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.51 (0.05) -0.038 0.507 ( -0.15, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.68 (0.07)

158 -0.80 (0.07) -0.122 0.104 ( -0.27, 0.03)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.74 (0.08)

156 -0.94 (0.08) -0.205 0.013 ( -0.37, -0.04)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -0.83 (0.08)

153 -1.06 (0.08) -0.229 0.009 ( -0.40, -0.06)

RM2008/00422/00

155 -0.47 (0.06)

CONFIDENTIAL

543

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.42 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Nasal Congestion ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.66 (0.06) -0.82 (0.06) LS Mean Difference -0.161 p-value vs. Placebo 0.018 95% C.I. ( -0.29, -0.03)

CONFIDENTIAL

544

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.43 Summary of PM Reflective Symptom Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.05) 2.3 (0.04) Median 2.3 2.3 Min - Max 0.0 - 3.0 0.5 - 3.0 155 -0.4 (0.05) -0.3 -2.3 - 2.1

160 1.8 (0.05) 1.9 0.1 - 3.0

160 -0.5 (0.05) -0.4 -2.9 - 0.9

Week 2 n Mean (Std Err) Median Min - Max

153 1.6 (0.06) 1.7 0.0 - 3.0

153 -0.6 (0.06) -0.5 -3.0 - 2.3

158 1.5 (0.06) 1.6 0.0 - 3.0

158 -0.8 (0.06) -0.7 -3.0 - 0.9

Week 3 n Mean (Std Err) Median Min - Max

151 1.6 (0.07) 1.7 0.0 - 3.0

151 -0.6 (0.07) -0.5 -3.0 - 2.1

156 1.3 (0.07) 1.3 0.0 - 3.0

156 -1.0 (0.07) -0.9 -3.0 - 0.7

Week 4 n Mean (Std Err) Median Min - Max

148 1.5 (0.07) 1.6 0.0 - 3.0

148 -0.7 (0.07) -0.7 -3.0 - 2.3

153 1.2 (0.07) 1.2 0.0 - 3.0

153 -1.1 (0.07) -1 -3.0 - 0.7

RM2008/00422/00

155 1.8 (0.06) 2 0.0 - 3.0

CONFIDENTIAL

545

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.43 Summary of PM Reflective Symptom Scores for Nasal Itching

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.6 (0.06) 1.5 (0.06) -0.8 (0.05) Median 1.8 -0.5 1.5 -0.8 Min - Max 0.0 - 3.0 -2.8 - 2.2 0.1 - 3.0 -2.9 - 0.5

CONFIDENTIAL

546

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.44 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.50 (0.06) -0.055 0.398 ( -0.18, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.69 (0.08)

158 -0.82 (0.08) -0.137 0.095 ( -0.30, 0.02)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.73 (0.08)

156 -1.02 (0.08) -0.295 <0.001 ( -0.47, -0.12)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -0.83 (0.09)

153 -1.15 (0.08) -0.324 <0.001 ( -0.50, -0.15)

RM2008/00422/00

155 -0.45 (0.06)

CONFIDENTIAL

547

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.44 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Nasal Itching ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.64 (0.07) -0.85 (0.07) LS Mean Difference -0.209 p-value vs. Placebo 0.004 95% C.I. ( -0.35, -0.07)

CONFIDENTIAL

548

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.45 Summary of PM Reflective Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.0 (0.05) 2.1 (0.05) Median 2 2 Min - Max 0.0 - 3.0 0.3 - 3.0 155 -0.4 (0.05) -0.3 -2.1 - 1.8

160 1.6 (0.06) 1.5 0.0 - 3.0

160 -0.5 (0.05) -0.4 -2.7 - 1.6

Week 2 n Mean (Std Err) Median Min - Max

153 1.4 (0.06) 1.4 0.0 - 3.0

153 -0.6 (0.06) -0.5 -3.0 - 2.1

158 1.3 (0.07) 1.1 0.0 - 3.0

158 -0.8 (0.06) -0.7 -3.0 - 1.3

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.07) 1.3 0.0 - 3.0

151 -0.6 (0.07) -0.6 -2.6 - 2.4

156 1.1 (0.07) 1 0.0 - 3.0

156 -1.0 (0.07) -1 -3.0 - 0.9

Week 4 n Mean (Std Err) Median Min - Max

148 1.3 (0.07) 1.2 0.0 - 3.0

148 -0.7 (0.07) -0.7 -2.8 - 2.5

153 1.0 (0.07) 1 0.0 - 3.0

153 -1.1 (0.07) -1 -3.0 - 0.8

RM2008/00422/00

155 1.6 (0.06) 1.6 0.0 - 3.0

CONFIDENTIAL

549

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.45 Summary of PM Reflective Symptom Scores for Sneezing

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.4 (0.06) -0.5 (0.06) 1.3 (0.06) -0.8 (0.06) Median 1.3 -0.5 1.1 -0.8 Min - Max 0.0 - 3.0 -2.3 - 2.2 0.0 - 3.0 -2.9 - 0.5

CONFIDENTIAL

550

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.46 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.51 (0.06) -0.058 0.376 ( -0.19, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.67 (0.08)

158 -0.84 (0.07) -0.168 0.035 ( -0.32, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.72 (0.08)

156 -1.03 (0.08) -0.309 <0.001 ( -0.48, -0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -0.84 (0.08)

153 -1.13 (0.08) -0.289 <0.001 ( -0.46, -0.12)

RM2008/00422/00

155 -0.45 (0.06)

CONFIDENTIAL

551

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.46 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Sneezing ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.65 (0.07) -0.87 (0.06) LS Mean Difference -0.220 p-value vs. Placebo 0.002 95% C.I. ( -0.36, -0.08)

CONFIDENTIAL

552

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.47 Summary of AM Pre-Dose Instantaneous Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 6.5 (0.13) 6.3 (0.14) Median 6.5 6.3 Min - Max 2.0 - 9.0 1.0 - 9.0 155 -1.3 (0.15) -0.8 -8.4 - 3.2

160 5.1 (0.16) 5.1 0.0 - 9.0

160 -1.1 (0.12) -0.7 -6.9 - 1.7

Week 2 n Mean (Std Err) Median Min - Max

153 4.7 (0.19) 4.9 0.0 - 9.0

153 -1.7 (0.18) -1.2 -8.5 - 3.5

158 4.5 (0.19) 4.6 0.0 - 9.0

158 -1.8 (0.17) -1.4 -7.4 - 3.5

Week 3 n Mean (Std Err) Median Min - Max

151 4.4 (0.20) 4.6 0.0 - 9.0

151 -2.0 (0.19) -1.7 -8.5 - 3.5

156 4.1 (0.20) 4 0.0 - 9.0

156 -2.2 (0.18) -2 -8.0 - 2.3

Week 4 n Mean (Std Err) Median Min - Max

149 4.2 (0.22) 4.4 0.0 - 9.0

149 -2.2 (0.21) -1.9 -9.0 - 4.2

153 3.9 (0.21) 3.7 0.0 - 9.0

153 -2.6 (0.19) -2.3 -9.0 - 2.0

RM2008/00422/00

155 5.2 (0.17) 5.1 0.0 - 9.0

CONFIDENTIAL

553

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.47 Summary of AM Pre-Dose Instantaneous Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 4.7 (0.18) -1.8 (0.17) 4.4 (0.17) -1.9 (0.15) Median 5 -1.2 4.3 -1.7 Min - Max 0.0 - 9.0 -8.5 - 3.5 0.0 - 9.0 -7.3 - 2.1

CONFIDENTIAL

554

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.48 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.19 (0.17) 0.082 0.655 ( -0.28, 0.44)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -1.77 (0.22)

158 -1.87 (0.21) -0.105 0.645 ( -0.55, 0.34)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.07 (0.24)

156 -2.34 (0.23) -0.273 0.268 ( -0.76, 0.21)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -2.28 (0.26)

153 -2.63 (0.24) -0.340 0.202 ( -0.86, 0.18)

RM2008/00422/00

155 -1.27 (0.18)

CONFIDENTIAL

555

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.48 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -1.80 (0.20) -1.97 (0.19) LS Mean Difference -0.173 p-value vs. Placebo 0.407 95% C.I. ( -0.58, 0.24)

CONFIDENTIAL

556

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.49 Summary of AM Reflective Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 6.5 (0.11) 6.3 (0.12) Median 6.5 6 Min - Max 3.5 - 9.0 0.7 - 9.0 155 -1.2 (0.14) -0.8 -8.7 - 3.0

160 5.2 (0.15) 5.2 0.0 - 9.0

160 -1.1 (0.11) -0.8 -5.8 - 1.5

Week 2 n Mean (Std Err) Median Min - Max

153 4.7 (0.18) 4.9 0.0 - 9.0

153 -1.8 (0.17) -1.5 -9.0 - 3.0

158 4.3 (0.18) 4.3 0.0 - 9.0

158 -2.0 (0.16) -1.8 -7.3 - 2.1

Week 3 n Mean (Std Err) Median Min - Max

151 4.4 (0.20) 4.5 0.0 - 9.0

151 -2.1 (0.19) -1.7 -9.0 - 3.0

156 4.0 (0.19) 4 0.0 - 9.0

156 -2.4 (0.18) -2.1 -8.0 - 2.7

Week 4 n Mean (Std Err) Median Min - Max

149 4.2 (0.21) 4.5 0.0 - 9.0

149 -2.3 (0.20) -2.1 -8.8 - 3.3

153 3.7 (0.21) 3.5 0.0 - 9.0

153 -2.8 (0.20) -2.6 -9.0 - 2.8

RM2008/00422/00

155 5.3 (0.17) 5.4 0.0 - 9.0

CONFIDENTIAL

557

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.49 Summary of AM Reflective Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 4.7 (0.18) -1.8 (0.16) 4.3 (0.17) -2.0 (0.15) Median 4.8 -1.5 4.2 -1.9 Min - Max 0.2 - 9.0 -8.8 - 2.8 0.0 - 9.0 -6.8 - 1.8

CONFIDENTIAL

558

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.50 Analysis of Mean Change from Baseline in AM Reflective Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.29 (0.16) 0.033 0.853 ( -0.31, 0.38)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -1.88 (0.21)

158 -2.14 (0.20) -0.254 0.251 ( -0.69, 0.18)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.21 (0.24)

156 -2.57 (0.23) -0.367 0.136 ( -0.85, 0.12)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -2.46 (0.26)

153 -2.94 (0.25) -0.477 0.076 ( -1.00, 0.05)

RM2008/00422/00

155 -1.32 (0.17)

CONFIDENTIAL

559

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.50 Analysis of Mean Change from Baseline in AM Reflective Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -1.92 (0.20) -2.19 (0.19) LS Mean Difference -0.271 p-value vs. Placebo 0.188 95% C.I. ( -0.67, 0.13)

CONFIDENTIAL

560

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.51 Summary of PM Reflective Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 6.6 (0.12) 6.3 (0.12) Median 6.5 6 Min - Max 3.5 - 9.0 1.0 - 9.0 155 -1.4 (0.14) -1.1 -7.3 - 3.6

160 5.1 (0.15) 5.1 0.1 - 9.0

160 -1.2 (0.12) -1 -6.8 - 2.0

Week 2 n Mean (Std Err) Median Min - Max

153 4.6 (0.19) 4.6 0.0 - 9.0

153 -2.0 (0.18) -1.7 -9.0 - 2.8

158 4.4 (0.18) 4.3 0.0 - 9.0

158 -2.0 (0.17) -1.6 -7.2 - 2.4

Week 3 n Mean (Std Err) Median Min - Max

151 4.4 (0.20) 4.7 0.0 - 9.0

151 -2.2 (0.19) -2 -8.1 - 2.8

156 3.9 (0.19) 3.7 0.0 - 9.0

156 -2.5 (0.19) -2.3 -8.0 - 3.1

Week 4 n Mean (Std Err) Median Min - Max

148 4.1 (0.21) 4.2 0.0 - 9.0

148 -2.5 (0.21) -2.2 -8.3 - 2.5

153 3.5 (0.20) 3.6 0.0 - 9.0

153 -2.9 (0.19) -2.8 -9.0 - 1.8

RM2008/00422/00

155 5.2 (0.16) 5.1 0.1 - 9.0

CONFIDENTIAL

561

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.51 Summary of PM Reflective Total Ocular Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 4.7 (0.18) -2.0 (0.17) 4.2 (0.16) -2.1 (0.15) Median 4.6 -1.7 4.1 -1.9 Min - Max 0.4 - 9.0 -8.0 - 2.6 0.3 - 9.0 -7.1 - 2.0

CONFIDENTIAL

562

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.52 Analysis of Mean Change from Baseline in PM Reflective Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -1.31 (0.16) 0.090 0.611 ( -0.26, 0.44)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -2.11 (0.22)

158 -2.19 (0.21) -0.081 0.727 ( -0.54, 0.37)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.38 (0.24)

156 -2.74 (0.23) -0.360 0.158 ( -0.86, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -2.60 (0.26)

153 -3.09 (0.25) -0.494 0.066 ( -1.02, 0.03)

RM2008/00422/00

155 -1.40 (0.17)

CONFIDENTIAL

563

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.52 Analysis of Mean Change from Baseline in PM Reflective Total Ocular Symptom Scores ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -2.05 (0.20) -2.28 (0.19) LS Mean Difference -0.238 p-value vs. Placebo 0.260 95% C.I. ( -0.65, 0.18)

CONFIDENTIAL

564

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.53 Summary of Daily Reflective Symptom Scores for Eye Itching/Burning

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.3 (0.04) 2.2 (0.04) Median 2.3 2.1 Min - Max 1.0 - 3.0 0.4 - 3.0 155 -0.4 (0.05) -0.3 -2.6 - 0.9

160 1.8 (0.05) 1.9 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.1 - 0.9

Week 2 n Mean (Std Err) Median Min - Max

153 1.7 (0.06) 1.9 0.0 - 3.0

153 -0.6 (0.06) -0.6 -3.0 - 0.9

158 1.6 (0.06) 1.6 0.0 - 3.0

158 -0.7 (0.06) -0.6 -2.4 - 1.1

Week 3 n Mean (Std Err) Median Min - Max

151 1.6 (0.06) 1.8 0.0 - 3.0

151 -0.7 (0.06) -0.6 -2.8 - 0.9

156 1.4 (0.07) 1.4 0.0 - 3.0

156 -0.8 (0.06) -0.8 -2.8 - 1.6

Week 4 n Mean (Std Err) Median Min - Max

149 1.5 (0.07) 1.7 0.0 - 3.0

149 -0.8 (0.07) -0.7 -2.9 - 0.9

153 1.3 (0.07) 1.2 0.0 - 3.0

153 -1.0 (0.07) -0.9 -3.0 - 0.8

RM2008/00422/00

155 1.9 (0.05) 2 0.1 - 3.0

CONFIDENTIAL

565

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.53 Summary of Daily Reflective Symptom Scores for Eye Itching/Burning

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.6 (0.05) 1.5 (0.06) -0.7 (0.05) Median 1.8 -0.5 1.5 -0.7 Min - Max 0.1 - 3.0 -2.8 - 0.8 0.0 - 3.0 -2.3 - 0.9

CONFIDENTIAL

566

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.54 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Itching/Burning ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.41 (0.05) 0.020 0.737 ( -0.10, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.65 (0.07)

158 -0.71 (0.07) -0.062 0.428 ( -0.21, 0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.73 (0.08)

156 -0.90 (0.08) -0.174 0.040 ( -0.34, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.85 (0.09)

153 -1.05 (0.08) -0.195 0.035 ( -0.38, -0.01)

RM2008/00422/00

155 -0.43 (0.06)

CONFIDENTIAL

567

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.54 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Itching/Burning ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.64 (0.07) -0.75 (0.06) LS Mean Difference -0.107 p-value vs. Placebo 0.130 95% C.I. ( -0.25, 0.03)

CONFIDENTIAL

568

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.55 Summary of Daily Reflective Symptom Score for Eye Tearing/Watering

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.04) 2.1 (0.05) Median 2.1 2 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.6 - 1.3

160 1.7 (0.05) 1.8 0.1 - 3.0

160 -0.4 (0.04) -0.3 -2.3 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.4 0.0 - 3.0

153 -0.7 (0.06) -0.6 -3.0 - 1.0

158 1.4 (0.06) 1.4 0.0 - 3.0

158 -0.7 (0.06) -0.6 -2.9 - 0.9

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.07) 1.4 0.0 - 3.0

151 -0.7 (0.06) -0.6 -2.7 - 1.0

156 1.3 (0.07) 1.2 0.0 - 3.0

156 -0.8 (0.06) -0.7 -2.9 - 1.1

Week 4 n Mean (Std Err) Median Min - Max

149 1.3 (0.07) 1.3 0.0 - 3.0

149 -0.8 (0.07) -0.7 -2.9 - 0.9

153 1.2 (0.07) 1.1 0.0 - 3.0

153 -1.0 (0.07) -0.9 -3.0 - 0.9

RM2008/00422/00

155 1.7 (0.06) 1.8 0.0 - 3.0

CONFIDENTIAL

569

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.55 Summary of Daily Reflective Symptom Score for Eye Tearing/Watering

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.5 (0.06) -0.6 (0.05) 1.4 (0.06) -0.7 (0.05) Median 1.4 -0.6 1.3 -0.6 Min - Max 0.0 - 3.0 -2.8 - 0.9 0.1 - 3.0 -2.6 - 0.9

CONFIDENTIAL

570

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.56 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.43 (0.05) 0.032 0.594 ( -0.09, 0.15)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.70 (0.07)

158 -0.73 (0.07) -0.036 0.640 ( -0.19, 0.11)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.80 (0.08)

156 -0.90 (0.08) -0.108 0.204 ( -0.27, 0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.86 (0.08)

153 -1.03 (0.08) -0.164 0.065 ( -0.34, 0.01)

RM2008/00422/00

155 -0.47 (0.06)

CONFIDENTIAL

571

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.56 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.69 (0.07) -0.76 (0.06) LS Mean Difference -0.072 p-value vs. Placebo 0.303 95% C.I. ( -0.21, 0.07)

CONFIDENTIAL

572

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.57 Summary of Daily Reflective Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.1 (0.05) 2.0 (0.05) Median 2 2 Min - Max 0.1 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.7 - 1.1

160 1.6 (0.05) 1.7 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.2 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.4 0.0 - 3.0

153 -0.6 (0.06) -0.5 -3.0 - 1.0

158 1.4 (0.06) 1.2 0.0 - 3.0

158 -0.7 (0.06) -0.6 -2.3 - 0.7

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.07) 1.4 0.0 - 3.0

151 -0.7 (0.07) -0.6 -2.8 - 1.0

156 1.3 (0.07) 1.1 0.0 - 3.0

156 -0.8 (0.06) -0.8 -2.6 - 0.9

Week 4 n Mean (Std Err) Median Min - Max

149 1.3 (0.08) 1.3 0.0 - 3.0

149 -0.8 (0.07) -0.7 -2.9 - 1.0

153 1.2 (0.07) 1 0.0 - 3.0

153 -0.9 (0.07) -0.9 -3.0 - 0.9

RM2008/00422/00

155 1.6 (0.06) 1.7 0.0 - 3.0

CONFIDENTIAL

573

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.57 Summary of Daily Reflective Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.5 (0.07) -0.6 (0.06) 1.4 (0.06) -0.7 (0.05) Median 1.4 -0.5 1.3 -0.7 Min - Max 0.0 - 3.0 -2.8 - 0.9 0.0 - 3.0 -2.4 - 0.5

CONFIDENTIAL

574

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.58 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.44 (0.06) 0.014 0.821 ( -0.11, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.66 (0.08)

158 -0.72 (0.07) -0.063 0.430 ( -0.22, 0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.76 (0.08)

156 -0.84 (0.08) -0.083 0.344 ( -0.26, 0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.82 (0.09)

153 -0.94 (0.09) -0.123 0.195 ( -0.31, 0.06)

RM2008/00422/00

155 -0.46 (0.06)

CONFIDENTIAL

575

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.58 Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.65 (0.07) -0.72 (0.07) LS Mean Difference -0.070 p-value vs. Placebo 0.341 95% C.I. ( -0.21, 0.07)

CONFIDENTIAL

576

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.59 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.3 (0.04) 2.2 (0.05) Median 2.3 2.3 Min - Max 0.5 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.9 - 0.8

160 1.8 (0.05) 2 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.3 - 0.7

Week 2 n Mean (Std Err) Median Min - Max

153 1.7 (0.06) 2 0.0 - 3.0

153 -0.6 (0.06) -0.4 -3.0 - 1.1

158 1.6 (0.07) 1.8 0.0 - 3.0

158 -0.6 (0.06) -0.5 -2.5 - 1.6

Week 3 n Mean (Std Err) Median Min - Max

151 1.6 (0.07) 1.9 0.0 - 3.0

151 -0.6 (0.07) -0.4 -3.0 - 1.3

156 1.5 (0.07) 1.5 0.0 - 3.0

156 -0.8 (0.06) -0.7 -2.7 - 1.2

Week 4 n Mean (Std Err) Median Min - Max

149 1.5 (0.07) 1.7 0.0 - 3.0

149 -0.7 (0.07) -0.7 -3.0 - 1.3

153 1.4 (0.07) 1.4 0.0 - 3.0

153 -0.9 (0.07) -0.8 -3.0 - 0.8

RM2008/00422/00

155 1.9 (0.06) 2 0.0 - 3.0

CONFIDENTIAL

577

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.59 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.6 (0.06) 1.6 (0.06) -0.6 (0.05) Median 1.9 -0.4 1.6 -0.6 Min - Max 0.0 - 3.0 -3.0 - 1.1 0.0 - 3.0 -2.5 - 1.0

CONFIDENTIAL

578

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.60 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.40 (0.06) 0.007 0.910 ( -0.12, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.58 (0.08)

158 -0.66 (0.08) -0.075 0.363 ( -0.24, 0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.65 (0.09)

156 -0.80 (0.08) -0.149 0.094 ( -0.32, 0.03)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.75 (0.09)

153 -0.90 (0.09) -0.148 0.119 ( -0.33, 0.04)

RM2008/00422/00

155 -0.41 (0.06)

CONFIDENTIAL

579

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.60 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.58 (0.07) -0.67 (0.07) LS Mean Difference -0.091 p-value vs. Placebo 0.217 95% C.I. ( -0.24, 0.05)

CONFIDENTIAL

580

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.61 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.1 (0.05) 2.1 (0.05) Median 2 2 Min - Max 0.3 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.8 - 1.4

160 1.7 (0.06) 1.8 0.0 - 3.0

160 -0.4 (0.05) -0.3 -2.5 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.6 0.0 - 3.0

153 -0.6 (0.06) -0.4 -2.8 - 1.0

158 1.5 (0.07) 1.6 0.0 - 3.0

158 -0.6 (0.06) -0.5 -2.7 - 1.2

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.07) 1.3 0.0 - 3.0

151 -0.7 (0.07) -0.6 -2.8 - 1.0

156 1.3 (0.07) 1.2 0.0 - 3.0

156 -0.7 (0.06) -0.8 -3.0 - 1.1

Week 4 n Mean (Std Err) Median Min - Max

149 1.3 (0.07) 1.4 0.0 - 3.0

149 -0.8 (0.07) -0.7 -3.0 - 1.0

153 1.3 (0.07) 1.1 0.0 - 3.0

153 -0.9 (0.07) -0.8 -3.0 - 0.9

RM2008/00422/00

155 1.7 (0.06) 1.7 0.0 - 3.0

CONFIDENTIAL

581

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.61 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.5 (0.06) -0.6 (0.06) 1.4 (0.06) -0.6 (0.05) Median 1.5 -0.5 1.4 -0.6 Min - Max 0.0 - 3.0 -2.8 - 0.9 0.0 - 3.0 -2.6 - 0.8

CONFIDENTIAL

582

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.62 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.40 (0.06) 0.037 0.578 ( -0.09, 0.17)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.61 (0.08)

158 -0.64 (0.07) -0.026 0.743 ( -0.18, 0.13)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.75 (0.08)

156 -0.80 (0.08) -0.056 0.514 ( -0.23, 0.11)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.81 (0.09)

153 -0.90 (0.08) -0.088 0.335 ( -0.27, 0.09)

RM2008/00422/00

155 -0.44 (0.06)

CONFIDENTIAL

583

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.62 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.63 (0.07) -0.67 (0.07) LS Mean Difference -0.048 p-value vs. Placebo 0.515 95% C.I. ( -0.19, 0.10)

CONFIDENTIAL

584

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.63 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.0 (0.06) 2.0 (0.05) Median 2 2 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.8 - 1.3

160 1.6 (0.06) 1.7 0.0 - 3.0

160 -0.4 (0.05) -0.3 -2.3 - 1.0

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.6 0.0 - 3.0

153 -0.6 (0.06) -0.4 -2.8 - 1.4

158 1.5 (0.07) 1.4 0.0 - 3.0

158 -0.6 (0.06) -0.4 -2.5 - 1.0

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.07) 1.3 0.0 - 3.0

151 -0.6 (0.07) -0.4 -2.8 - 1.3

156 1.3 (0.07) 1.2 0.0 - 3.0

156 -0.7 (0.06) -0.7 -2.8 - 0.8

Week 4 n Mean (Std Err) Median Min - Max

149 1.3 (0.08) 1.3 0.0 - 3.0

149 -0.7 (0.07) -0.7 -3.0 - 1.8

153 1.2 (0.07) 1 0.0 - 3.0

153 -0.8 (0.07) -0.8 -3.0 - 1.0

RM2008/00422/00

155 1.6 (0.07) 1.6 0.0 - 3.0

CONFIDENTIAL

585

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.63 Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.5 (0.07) -0.6 (0.06) 1.4 (0.06) -0.6 (0.05) Median 1.5 -0.4 1.3 -0.5 Min - Max 0.0 - 3.0 -2.8 - 1.5 0.0 - 3.0 -2.5 - 0.7

CONFIDENTIAL

586

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.64 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.40 (0.06) 0.032 0.630 ( -0.10, 0.16)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.58 (0.08)

158 -0.59 (0.07) -0.008 0.917 ( -0.17, 0.15)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.68 (0.08)

156 -0.75 (0.08) -0.072 0.401 ( -0.24, 0.10)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.73 (0.09)

153 -0.83 (0.09) -0.103 0.281 ( -0.29, 0.09)

RM2008/00422/00

155 -0.43 (0.06)

CONFIDENTIAL

587

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.64 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.59 (0.07) -0.63 (0.07) LS Mean Difference -0.042 p-value vs. Placebo 0.567 95% C.I. ( -0.19, 0.10)

CONFIDENTIAL

588

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.65 Summary of AM Reflective Symptom Scores for Eye Itching/Burning

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.3 (0.04) 2.2 (0.04) Median 2.3 2.1 Min - Max 1.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.9 - 0.8

160 1.8 (0.05) 1.9 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.1 - 1.0

Week 2 n Mean (Std Err) Median Min - Max

153 1.7 (0.06) 1.9 0.0 - 3.0

153 -0.6 (0.06) -0.5 -3.0 - 1.0

158 1.6 (0.06) 1.6 0.0 - 3.0

158 -0.7 (0.06) -0.7 -2.4 - 1.2

Week 3 n Mean (Std Err) Median Min - Max

151 1.6 (0.07) 1.7 0.0 - 3.0

151 -0.7 (0.06) -0.6 -3.0 - 1.0

156 1.4 (0.07) 1.4 0.0 - 3.0

156 -0.8 (0.06) -0.7 -3.0 - 1.8

Week 4 n Mean (Std Err) Median Min - Max

149 1.5 (0.07) 1.7 0.0 - 3.0

149 -0.8 (0.07) -0.8 -3.0 - 1.2

153 1.3 (0.07) 1.3 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 0.9

RM2008/00422/00

155 1.9 (0.06) 2 0.0 - 3.0

CONFIDENTIAL

589

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.65 Summary of AM Reflective Symptom Scores for Eye Itching/Burning

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.6 (0.06) 1.5 (0.06) -0.7 (0.05) Median 1.9 -0.5 1.5 -0.6 Min - Max 0.1 - 3.0 -2.9 - 0.9 0.0 - 3.0 -2.4 - 1.0

CONFIDENTIAL

590

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.66 Anlalysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Itching/Burning ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.42 (0.06) -0.009 0.885 ( -0.13, 0.11)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.60 (0.07)

158 -0.71 (0.07) -0.105 0.178 ( -0.26, 0.05)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.72 (0.08)

156 -0.89 (0.08) -0.174 0.043 ( -0.34, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.85 (0.09)

153 -1.03 (0.09) -0.184 0.052 ( -0.37, 0.00)

RM2008/00422/00

155 -0.41 (0.06)

CONFIDENTIAL

591

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.66 Anlalysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Itching/Burning ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.62 (0.07) -0.74 (0.07) LS Mean Difference -0.119 p-value vs. Placebo 0.095 95% C.I. ( -0.26, 0.02)

CONFIDENTIAL

592

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.67 Summary of AM Reflective Symptom Scores for Eye Tearing/Watering

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.05) 2.0 (0.05) Median 2 2 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.4 (0.05) -0.3 -2.9 - 1.2

160 1.7 (0.06) 1.7 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.0 - 0.8

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.4 0.0 - 3.0

153 -0.6 (0.06) -0.6 -3.0 - 1.0

158 1.4 (0.06) 1.4 0.0 - 3.0

158 -0.7 (0.06) -0.6 -2.5 - 0.6

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.07) 1.4 0.0 - 3.0

151 -0.7 (0.06) -0.7 -3.0 - 1.0

156 1.3 (0.07) 1.2 0.0 - 3.0

156 -0.8 (0.06) -0.7 -3.0 - 0.9

Week 4 n Mean (Std Err) Median Min - Max

149 1.4 (0.07) 1.4 0.0 - 3.0

149 -0.8 (0.07) -0.7 -3.0 - 1.0

153 1.2 (0.07) 1 0.0 - 3.0

153 -0.9 (0.07) -0.8 -3.0 - 1.0

RM2008/00422/00

155 1.8 (0.06) 1.9 0.0 - 3.0

CONFIDENTIAL

593

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.67 Summary of AM Reflective Symptom Scores for Eye Tearing/Watering

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.6 (0.06) -0.6 (0.05) 1.4 (0.06) -0.7 (0.05) Median 1.6 -0.6 1.3 -0.6 Min - Max 0.0 - 3.0 -2.9 - 0.9 0.0 - 3.0 -2.5 - 0.8

CONFIDENTIAL

594

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.68 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.43 (0.06) 0.024 0.704 ( -0.10, 0.15)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.66 (0.07)

158 -0.72 (0.07) -0.062 0.422 ( -0.21, 0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.77 (0.08)

156 -0.87 (0.08) -0.105 0.216 ( -0.27, 0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.84 (0.09)

153 -0.99 (0.08) -0.159 0.081 ( -0.34, 0.02)

RM2008/00422/00

155 -0.45 (0.06)

CONFIDENTIAL

595

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.68 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.66 (0.07) -0.74 (0.06) LS Mean Difference -0.080 p-value vs. Placebo 0.253 95% C.I. ( -0.22, 0.06)

CONFIDENTIAL

596

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.69 Summary of AM Reflective Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.1 (0.05) 2.0 (0.05) Median 2 2 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.4 (0.06) -0.3 -3.0 - 1.1

160 1.6 (0.06) 1.7 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.1 - 0.7

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.6 0.0 - 3.0

153 -0.6 (0.06) -0.4 -3.0 - 1.1

158 1.4 (0.07) 1.2 0.0 - 3.0

158 -0.7 (0.06) -0.6 -2.4 - 0.8

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.08) 1.3 0.0 - 3.0

151 -0.7 (0.07) -0.6 -3.0 - 1.1

156 1.3 (0.07) 1.1 0.0 - 3.0

156 -0.8 (0.06) -0.8 -2.7 - 0.9

Week 4 n Mean (Std Err) Median Min - Max

149 1.3 (0.08) 1.2 0.0 - 3.0

149 -0.7 (0.07) -0.7 -2.9 - 1.5

153 1.2 (0.07) 1 0.0 - 3.0

153 -0.9 (0.07) -0.9 -3.0 - 1.0

RM2008/00422/00

155 1.6 (0.07) 1.7 0.0 - 3.0

CONFIDENTIAL

597

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.69 Summary of AM Reflective Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.5 (0.07) -0.6 (0.06) 1.4 (0.06) -0.7 (0.05) Median 1.5 -0.5 1.3 -0.6 Min - Max 0.0 - 3.0 -3.0 - 1.1 0.0 - 3.0 -2.5 - 0.6

CONFIDENTIAL

598

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.70 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.45 (0.06) 0.009 0.887 ( -0.12, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.63 (0.08)

158 -0.72 (0.07) -0.094 0.244 ( -0.25, 0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.72 (0.08)

156 -0.82 (0.08) -0.097 0.273 ( -0.27, 0.08)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -0.78 (0.09)

153 -0.92 (0.09) -0.136 0.160 ( -0.33, 0.05)

RM2008/00422/00

155 -0.46 (0.06)

CONFIDENTIAL

599

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.70 Analysis of Mean Change from Baseline in AM Reflective Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.63 (0.07) -0.72 (0.07) LS Mean Difference -0.082 p-value vs. Placebo 0.270 95% C.I. ( -0.23, 0.06)

CONFIDENTIAL

600

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.71 Summary of PM Reflective Symptom Scores for Eye Itching/Burning

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.3 (0.04) 2.2 (0.04) Median 2.3 2.1 Min - Max 1.0 - 3.0 0.5 - 3.0 155 -0.4 (0.05) -0.4 -2.4 - 1.0

160 1.8 (0.05) 1.9 0.0 - 3.0

160 -0.4 (0.04) -0.3 -2.1 - 1.0

Week 2 n Mean (Std Err) Median Min - Max

153 1.7 (0.06) 1.7 0.0 - 3.0

153 -0.7 (0.06) -0.6 -3.0 - 1.0

158 1.6 (0.06) 1.6 0.0 - 3.0

158 -0.6 (0.06) -0.6 -2.6 - 1.1

Week 3 n Mean (Std Err) Median Min - Max

151 1.6 (0.07) 1.7 0.0 - 3.0

151 -0.7 (0.07) -0.6 -2.8 - 1.0

156 1.4 (0.07) 1.4 0.0 - 3.0

156 -0.8 (0.06) -0.8 -2.7 - 1.6

Week 4 n Mean (Std Err) Median Min - Max

148 1.5 (0.07) 1.6 0.0 - 3.0

148 -0.8 (0.07) -0.8 -3.0 - 1.0

153 1.3 (0.07) 1.3 0.0 - 3.0

153 -1.0 (0.07) -1 -3.0 - 0.8

RM2008/00422/00

155 1.9 (0.05) 2 0.1 - 3.0

CONFIDENTIAL

601

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.71 Summary of PM Reflective Symptom Scores for Eye Itching/Burning

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.7 (0.06) -0.6 (0.06) 1.5 (0.06) -0.7 (0.05) Median 1.8 -0.6 1.5 -0.7 Min - Max 0.1 - 3.0 -2.7 - 1.0 0.0 - 3.0 -2.4 - 0.9

CONFIDENTIAL

602

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.72 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Itching/Buring ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.42 (0.06) 0.026 0.676 ( -0.10, 0.15)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.68 (0.08)

158 -0.72 (0.08) -0.035 0.671 ( -0.20, 0.13)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.74 (0.08)

156 -0.92 (0.08) -0.186 0.035 ( -0.36, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -0.85 (0.09)

153 -1.07 (0.09) -0.219 0.022 ( -0.40, -0.03)

RM2008/00422/00

155 -0.45 (0.06)

CONFIDENTIAL

603

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.72 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Itching/Buring ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.66 (0.07) -0.77 (0.07) LS Mean Difference -0.113 p-value vs. Placebo 0.121 95% C.I. ( -0.26, 0.03)

CONFIDENTIAL

604

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.73 Summary of PM Reflective Symptom Scores for Eye Tearing/Watering

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.2 (0.05) 2.1 (0.05) Median 2 2 Min - Max 0.0 - 3.0 0.0 - 3.0 155 -0.5 (0.05) -0.5 -2.4 - 1.4

160 1.6 (0.05) 1.7 0.0 - 3.0

160 -0.4 (0.05) -0.3 -2.5 - 1.1

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.3 0.0 - 3.0

153 -0.7 (0.06) -0.7 -3.0 - 1.1

158 1.4 (0.06) 1.3 0.0 - 3.0

158 -0.7 (0.06) -0.6 -3.0 - 1.3

Week 3 n Mean (Std Err) Median Min - Max

151 1.4 (0.07) 1.3 0.0 - 3.0

151 -0.8 (0.07) -0.8 -3.0 - 1.0

156 1.2 (0.07) 1.2 0.0 - 3.0

156 -0.8 (0.07) -0.8 -3.0 - 1.3

Week 4 n Mean (Std Err) Median Min - Max

148 1.3 (0.07) 1.3 0.0 - 3.0

148 -0.8 (0.07) -0.8 -2.8 - 0.9

153 1.1 (0.07) 1 0.0 - 3.0

153 -1.0 (0.07) -0.9 -3.0 - 1.3

RM2008/00422/00

155 1.7 (0.06) 1.7 0.0 - 3.0

CONFIDENTIAL

605

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.73 Summary of PM Reflective Symptom Scores for Eye Tearing/Watering

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.5 (0.06) -0.7 (0.06) 1.4 (0.06) -0.7 (0.05) Median 1.4 -0.6 1.3 -0.7 Min - Max 0.0 - 3.0 -2.8 - 0.9 0.0 - 3.0 -2.9 - 1.2

CONFIDENTIAL

606

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.74 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.46 (0.06) 0.043 0.502 ( -0.08, 0.17)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.74 (0.08)

158 -0.75 (0.07) -0.012 0.880 ( -0.17, 0.15)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.83 (0.09)

156 -0.94 (0.08) -0.108 0.227 ( -0.28, 0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -0.89 (0.09)

153 -1.06 (0.08) -0.171 0.061 ( -0.35, 0.01)

RM2008/00422/00

155 -0.50 (0.06)

CONFIDENTIAL

607

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.74 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Tearing/Watering ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.72 (0.07) -0.79 (0.07) LS Mean Difference -0.070 p-value vs. Placebo 0.338 95% C.I. ( -0.21, 0.07)

CONFIDENTIAL

608

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.75 Summary of PM Reflective Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 2.1 (0.05) 2.0 (0.05) Median 2 2 Min - Max 0.3 - 3.0 0.0 - 3.0 155 -0.5 (0.05) -0.3 -2.7 - 1.2

160 1.6 (0.06) 1.7 0.0 - 3.0

160 -0.4 (0.04) -0.4 -2.3 - 1.0

Week 2 n Mean (Std Err) Median Min - Max

153 1.5 (0.07) 1.6 0.0 - 3.0

153 -0.6 (0.07) -0.5 -3.0 - 1.0

158 1.4 (0.06) 1.3 0.0 - 3.0

158 -0.7 (0.06) -0.5 -2.3 - 0.9

Week 3 n Mean (Std Err) Median Min - Max

151 1.3 (0.07) 1.3 0.0 - 3.0

151 -0.8 (0.07) -0.7 -2.8 - 1.0

156 1.2 (0.07) 1.1 0.0 - 3.0

156 -0.8 (0.07) -0.8 -2.8 - 1.2

Week 4 n Mean (Std Err) Median Min - Max

148 1.3 (0.08) 1.2 0.0 - 3.0

148 -0.8 (0.08) -0.7 -2.8 - 1.0

153 1.1 (0.07) 1 0.0 - 3.0

153 -0.9 (0.07) -0.9 -3.0 - 1.0

RM2008/00422/00

155 1.7 (0.06) 1.7 0.0 - 3.0

CONFIDENTIAL

609

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.75 Summary of PM Reflective Symptom Scores for Eye Redness

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 1.5 (0.07) -0.7 (0.06) 1.3 (0.06) -0.7 (0.05) Median 1.5 -0.6 1.3 -0.6 Min - Max 0.0 - 3.0 -2.7 - 0.9 0.0 - 3.0 -2.4 - 0.8

CONFIDENTIAL

610

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.76 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 -0.44 (0.06) 0.012 0.849 ( -0.11, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 -0.68 (0.08)

158 -0.72 (0.08) -0.044 0.592 ( -0.21, 0.12)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -0.81 (0.09)

156 -0.88 (0.08) -0.072 0.427 ( -0.25, 0.11)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -0.85 (0.09)

153 -0.96 (0.09) -0.110 0.260 ( -0.30, 0.08)

RM2008/00422/00

155 -0.45 (0.06)

CONFIDENTIAL

611

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.76 Analysis of Mean Change from Baseline in PM Reflective Symptom Scores for Eye Redness ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) -0.67 (0.07) -0.73 (0.07) LS Mean Difference -0.065 p-value vs. Placebo 0.389 95% C.I. ( -0.21, 0.08)

CONFIDENTIAL

612

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.77 Summary of Daily Peak Nasal Inspiratory Flow

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 95.0 (3.78) 96.3 (3.06) Median 88.8 90 Min - Max 23.8 - 305.0 18.8 - 277.5 155 7.1 (1.25) 4.3 -40.4 - 79.1

160 106.4 (3.02) 98.6 37.9 - 292.1

160 10.0 (1.23) 8 -38.9 - 90.7

Week 2 n Mean (Std Err) Median Min - Max

153 106.5 (4.08) 100.7 17.9 - 327.9

153 11.5 (1.75) 7.1 -42.9 - 104.1

158 115.1 (3.18) 108.2 34.3 - 288.6

158 18.3 (1.94) 13.5 -42.1 - 150.0

Week 3 n Mean (Std Err) Median Min - Max

151 108.4 (4.08) 100.7 15.7 - 325.7

151 13.6 (2.06) 8 -26.4 - 114.6

156 119.0 (3.31) 111.8 42.1 - 273.6

156 21.5 (2.33) 16.5 -36.4 - 145.7

Week 4 n Mean (Std Err) Median Min - Max

149 110.0 (4.10) 99.3 10.8 - 320.0

149 15.5 (2.39) 8.8 -44.3 - 140.4

153 121.2 (3.53) 114.2 41.4 - 297.1

153 24.3 (2.52) 21.3 -52.9 - 148.6

RM2008/00422/00

155 102.2 (3.89) 99.3 7.9 - 300.0

CONFIDENTIAL

613

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.77 Summary of Daily Peak Nasal Inspiratory Flow

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 106.5 (3.91) 11.5 (1.71) 114.6 (3.12) 18.3 (1.82) Median 100 6.6 108.9 14.2 Min - Max 13.1 - 318.4 -30.7 - 100.9 42.0 - 287.9 -37.5 - 132.9

CONFIDENTIAL

614

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.78 Analysis of Mean Change from Baseline in Daily Peak Nasal Inspiratory Flow ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 10.73 (1.58) 2.635 0.124 ( -0.73, 6.00)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 13.52 (2.45)

158 20.02 (2.34) 6.500 0.011 ( 1.53, 11.47)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 16.16 (2.87)

156 24.04 (2.75) 7.881 0.009 ( 2.01, 13.75)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 17.72 (3.18)

153 26.28 (3.03) 8.557 0.010 ( 2.04, 15.07)

RM2008/00422/00

155 8.10 (1.64)

CONFIDENTIAL

615

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.78 Analysis of Mean Change from Baseline in Daily Peak Nasal Inspiratory Flow

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) 13.52 (2.29) 19.98 (2.20) LS Mean Difference 6.458 p-value vs. Placebo 0.007 95% C.I. ( 1.77, 11.15)

CONFIDENTIAL

616

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.79 Summary of AM Peak Nasal Inspiratory Flow

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 91.8 (3.60) 93.2 (3.08) Median 85 87.5 Min - Max 20.0 - 295.0 2.5 - 265.0 155 7.4 (1.41) 3.6 -45.7 - 93.6

160 103.0 (3.05) 96.4 31.4 - 295.7

160 9.8 (1.36) 6.4 -34.3 - 92.9

Week 2 n Mean (Std Err) Median Min - Max

153 103.3 (4.04) 98.3 18.6 - 322.9

153 11.5 (1.86) 7.1 -31.7 - 109.2

158 111.7 (3.13) 105 32.5 - 287.1

158 18.1 (1.99) 12.5 -50.7 - 142.9

Week 3 n Mean (Std Err) Median Min - Max

151 104.4 (3.94) 98.3 15.7 - 321.4

151 12.9 (2.08) 6.4 -28.2 - 111.8

156 115.9 (3.27) 111.4 40.0 - 273.3

156 21.6 (2.35) 15 -33.9 - 143.9

Week 4 n Mean (Std Err) Median Min - Max

149 106.2 (3.95) 100 10.0 - 318.6

149 15.0 (2.36) 9.6 -46.5 - 131.4

153 117.6 (3.47) 108.6 41.4 - 300.0

153 23.9 (2.53) 20 -56.4 - 145.7

RM2008/00422/00

155 99.2 (3.85) 92.9 10.0 - 297.1

CONFIDENTIAL

617

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.79 Summary of AM Peak Nasal Inspiratory Flow

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 103.1 (3.81) 11.3 (1.72) 111.2 (3.09) 18.1 (1.88) Median 96.8 6.1 104.1 12.1 Min - Max 13.7 - 315.0 -30.0 - 107.1 38.9 - 289.6 -42.5 - 129.3

CONFIDENTIAL

618

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.80 Analysis of Mean Change from Baseline in AM Peak Nasal Inspiratory Flow ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 10.14 (1.79) 2.124 0.274 ( -1.69, 5.94)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 13.21 (2.57)

158 19.51 (2.46) 6.301 0.018 ( 1.08, 11.53)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 15.51 (2.90)

156 24.27 (2.78) 8.759 0.004 ( 2.83, 14.69)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 17.39 (3.18)

153 26.10 (3.04) 8.713 0.009 ( 2.19, 15.24)

RM2008/00422/00

155 8.01 (1.86)

CONFIDENTIAL

619

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.80 Analysis of Mean Change from Baseline in AM Peak Nasal Inspiratory Flow

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) 13.15 (2.36) 19.67 (2.27) LS Mean Difference 6.520 p-value vs. Placebo 0.008 95% C.I. ( 1.69, 11.35)

CONFIDENTIAL

620

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 7.81 Summary of PM Peak Nasal Inspiratory Flow

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 98.5 (4.07) 99.6 (3.14) Median 95 95 Min - Max 27.5 - 315.0 35.0 - 290.0 155 6.8 (1.39) 3.8 -35.0 - 80.4

160 109.5 (3.07) 101.4 42.9 - 288.6

160 9.9 (1.33) 7.7 -61.8 - 86.1

Week 2 n Mean (Std Err) Median Min - Max

153 109.7 (4.22) 102.9 17.1 - 332.9

153 11.3 (1.89) 5.2 -67.5 - 102.1

158 118.6 (3.29) 110.7 37.1 - 291.7

158 18.4 (2.03) 15.7 -33.6 - 154.6

Week 3 n Mean (Std Err) Median Min - Max

151 113.1 (4.43) 104.3 15.7 - 330.0

151 14.9 (2.19) 7.9 -32.1 - 132.1

156 122.3 (3.44) 114.3 44.3 - 277.1

156 21.5 (2.43) 17 -45.7 - 149.2

Week 4 n Mean (Std Err) Median Min - Max

148 114.1 (4.38) 102.9 11.7 - 321.4

148 16.0 (2.56) 7.7 -59.3 - 166.4

153 124.7 (3.65) 118.3 41.4 - 294.3

153 24.6 (2.61) 20 -58.6 - 148.9

RM2008/00422/00

155 105.3 (4.05) 98.6 5.7 - 302.9

CONFIDENTIAL

621

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 7.81 Summary of PM Peak Nasal Inspiratory Flow

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 110.1 (4.12) 11.7 (1.84) 117.9 (3.20) 18.3 (1.87) Median 103.8 6.8 110.7 15.8 Min - Max 12.6 - 321.8 -36.7 - 108.9 45.0 - 287.8 -37.9 - 133.9

CONFIDENTIAL

622

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.82 Analysis of Mean Change from Baseline in PM Peak Nasal Inspiratory Flow ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Week 1

Week 2

Week 4

160 10.90 (1.70) 2.715 0.141 ( -0.91, 6.34)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

153 13.61 (2.57)

158 20.29 (2.46) 6.685 0.012 ( 1.45, 11.92)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 17.49 (3.02)

156 23.99 (2.89) 6.499 0.039 ( 0.33, 12.67)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 18.17 (3.31)

153 26.36 (3.16) 8.183 0.018 ( 1.39, 14.98)

RM2008/00422/00

155 8.19 (1.77)

CONFIDENTIAL

623

Week 3

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.82 Analysis of Mean Change from Baseline in PM Peak Nasal Inspiratory Flow

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ---------------------------------------------------------------Weeks 1-4 n 155 160 LS Mean (Std Err) 13.88 (2.38) 20.05 (2.28) LS Mean Difference 6.175 p-value vs. Placebo 0.013 95% C.I. ( 1.31, 11.04)

CONFIDENTIAL

624

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 6

Table 7.83 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 8.7 (0.16) 8.9 (0.16) Median 8.8 9 Min - Max 3.5 - 12.0 2.0 - 12.0 150 -0.9 (0.19) -0.5 -9.8 - 4.8

159 8.0 (0.20) 8 1.0 - 12.0

159 -0.9 (0.14) -0.5 -7.0 - 3.3

Day 2 n Mean (Std Err) Median Min - Max

151 7.5 (0.21) 8 0.0 - 12.0

151 -1.2 (0.17) -0.8 -10.0 - 4.0

154 7.8 (0.20) 8 1.0 - 12.0

154 -1.1 (0.15) -1 -7.0 - 4.3

Day 3 n Mean (Std Err) Median Min - Max

147 7.3 (0.24) 7 1.0 - 12.0

147 -1.4 (0.21) -1 -10.8 - 4.8

155 7.2 (0.23) 7 1.0 - 12.0

155 -1.7 (0.19) -1.3 -9.0 - 3.3

Day 4 n Mean (Std Err) Median Min - Max

143 7.2 (0.24) 7 1.0 - 12.0

143 -1.4 (0.21) -1 -10.8 - 4.0

148 6.8 (0.25) 7 0.0 - 12.0

148 -2.0 (0.21) -2 -10.0 - 3.5

RM2008/00422/00

150 7.8 (0.22) 8 0.0 - 12.0

CONFIDENTIAL

625

Day 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 6

Table 7.83 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 5 n 149 149 154 154 Mean (Std Err) 7.0 (0.25) -1.7 (0.22) 7.0 (0.24) -2.0 (0.21) Median 7 -1.3 7 -1.6 Min - Max 0.0 - 12.0 -11.0 - 4.0 0.0 - 12.0 -10.0 - 4.5 146 -1.6 (0.24) -1 -11.0 - 4.8

155 6.7 (0.23) 7 0.0 - 12.0

155 -2.1 (0.20) -2 -9.0 - 4.5

Day 7 n Mean (Std Err) Median Min - Max

149 6.8 (0.25) 7 1.0 - 12.0

149 -1.8 (0.23) -1.3 -11.0 - 3.8

151 6.5 (0.23) 7 0.0 - 12.0

151 -2.4 (0.21) -2 -10.0 - 3.5

Day 8 n Mean (Std Err) Median Min - Max

148 6.7 (0.25) 7 0.0 - 12.0

148 -1.9 (0.24) -1.3 -10.0 - 5.8

149 6.4 (0.26) 7 0.0 - 12.0

149 -2.5 (0.24) -2.3 -11.0 - 3.5

Day 9 n Mean (Std Err) Median Min - Max

150 6.7 (0.23) 7 1.0 - 12.0

150 -2.0 (0.23) -1.5 -11.0 - 3.8

149 6.2 (0.25) 6 0.0 - 12.0

149 -2.7 (0.22) -2.5 -9.0 - 2.3

RM2008/00422/00

146 7.0 (0.25) 7 0.0 - 12.0

CONFIDENTIAL

626

Day 6 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 6

Table 7.83 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 10 n 147 147 148 148 Mean (Std Err) 6.7 (0.25) -1.9 (0.24) 6.3 (0.27) -2.6 (0.25) Median 7 -1.5 6 -2.3 Min - Max 0.0 - 12.0 -11.8 - 3.8 0.0 - 12.0 -10.0 - 6.3 143 -2.0 (0.26) -1.5 -11.8 - 4.5

151 6.0 (0.25) 6 0.0 - 12.0

151 -2.9 (0.23) -2.5 -9.5 - 2.3

Day 12 n Mean (Std Err) Median Min - Max

144 6.6 (0.25) 7 0.0 - 12.0

144 -2.0 (0.24) -1.4 -11.0 - 4.0

142 6.1 (0.27) 6 0.0 - 12.0

142 -2.9 (0.24) -2.6 -9.0 - 5.3

Day 13 n Mean (Std Err) Median Min - Max

145 6.4 (0.27) 6 0.0 - 12.0

145 -2.2 (0.26) -1.7 -11.8 - 4.8

149 6.0 (0.28) 6 0.0 - 12.0

149 -2.9 (0.25) -2.7 -10.8 - 3.0

Day 14 n Mean (Std Err) Median Min - Max

145 6.5 (0.26) 7 0.0 - 12.0

145 -2.1 (0.24) -1.7 -11.8 - 5.8

153 5.6 (0.27) 5 0.0 - 12.0

153 -3.3 (0.25) -3 -10.0 - 4.0

RM2008/00422/00

143 6.6 (0.27) 7 0.0 - 12.0

CONFIDENTIAL

627

Day 11 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 6

Table 7.83 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 15 n 143 143 147 147 Mean (Std Err) 6.3 (0.28) -2.3 (0.27) 5.6 (0.27) -3.2 (0.25) Median 7 -1.8 5 -3 Min - Max 0.0 - 12.0 -11.0 - 4.8 0.0 - 12.0 -11.0 - 3.5 141 -2.3 (0.27) -1.5 -11.0 - 5.8

150 5.7 (0.27) 6 0.0 - 12.0

150 -3.2 (0.25) -3 -12.0 - 3.0

Day 17 n Mean (Std Err) Median Min - Max

142 6.2 (0.27) 6 0.0 - 12.0

142 -2.4 (0.27) -1.6 -12.0 - 5.8

147 5.8 (0.27) 6 0.0 - 12.0

147 -3.1 (0.24) -3 -9.8 - 3.0

Day 18 n Mean (Std Err) Median Min - Max

140 6.1 (0.27) 6 0.0 - 12.0

140 -2.5 (0.27) -1.9 -11.8 - 3.8

152 5.4 (0.26) 5 0.0 - 12.0

152 -3.5 (0.25) -3.5 -12.0 - 4.0

Day 19 n Mean (Std Err) Median Min - Max

142 6.2 (0.28) 6 0.0 - 12.0

142 -2.4 (0.27) -1.7 -11.0 - 4.0

145 5.7 (0.28) 5 0.0 - 12.0

145 -3.3 (0.26) -3.3 -9.8 - 4.3

RM2008/00422/00

141 6.3 (0.26) 6 0.0 - 12.0

CONFIDENTIAL

628

Day 16 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 6

Table 7.83 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 20 n 141 141 149 149 Mean (Std Err) 6.1 (0.27) -2.5 (0.27) 5.3 (0.27) -3.6 (0.26) Median 7 -2 5 -3.3 Min - Max 0.0 - 12.0 -11.8 - 4.0 0.0 - 12.0 -12.0 - 3.8 142 -2.5 (0.27) -1.8 -11.8 - 5.8

148 5.1 (0.26) 5 0.0 - 12.0

148 -3.8 (0.25) -3.8 -12.0 - 3.7

Day 22 n Mean (Std Err) Median Min - Max

142 6.0 (0.27) 6 0.0 - 12.0

142 -2.6 (0.27) -2 -11.8 - 5.8

145 5.3 (0.27) 5 0.0 - 12.0

145 -3.7 (0.27) -3.5 -12.0 - 3.0

Day 23 n Mean (Std Err) Median Min - Max

133 5.9 (0.27) 6 0.0 - 12.0

133 -2.7 (0.29) -1.8 -11.8 - 5.8

141 5.4 (0.29) 5 0.0 - 12.0

141 -3.6 (0.27) -3.3 -12.0 - 5.8

Day 24 n Mean (Std Err) Median Min - Max

141 5.8 (0.26) 6 0.0 - 12.0

141 -2.8 (0.27) -2 -11.0 - 5.8

143 5.3 (0.29) 5 0.0 - 12.0

143 -3.7 (0.29) -3.8 -12.0 - 5.3

RM2008/00422/00

142 6.1 (0.27) 6 0.0 - 12.0

CONFIDENTIAL

629

Day 21 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 6

Table 7.83 Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 25 n 134 134 143 143 Mean (Std Err) 6.0 (0.27) -2.6 (0.27) 5.1 (0.30) -3.9 (0.27) Median 6 -2.3 5 -3.8 Min - Max 0.0 - 12.0 -11.8 - 5.8 0.0 - 12.0 -12.0 - 3.0 130 6.0 (0.29) 6 0.0 - 12.0

130 -2.6 (0.31) -2 -11.8 - 5.8

137 5.2 (0.29) 5 0.0 - 12.0

137 -3.8 (0.27) -3.8 -12.0 - 2.8

Day 27 n Mean (Std Err) Median Min - Max

122 6.0 (0.30) 6 0.0 - 12.0

122 -2.7 (0.32) -2.1 -11.8 - 5.8

124 5.3 (0.31) 5 0.0 - 12.0

124 -3.8 (0.28) -3.7 -12.0 - 2.3

Day 28 n Mean (Std Err) Median Min - Max

108 5.9 (0.32) 6 0.0 - 12.0

108 -2.8 (0.33) -2.1 -11.8 - 3.5

113 5.3 (0.33) 5 0.0 - 12.0

113 -3.9 (0.31) -3.8 -11.0 - 3.3

CONFIDENTIAL

630

Day 26 n Mean (Std Err) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 7

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

Day 1

Day 2

Day 4

150 -1.01 (0.22)

159 -0.98 (0.21) 0.022 0.924 ( -0.43, 0.47)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -1.28 (0.22)

154 -1.17 (0.21) 0.116 0.611 ( -0.33, 0.57)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -1.34 (0.27)

155 -1.61 (0.25) -0.266 0.340 ( -0.81, 0.28)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

143 -1.48 (0.28)

148 -2.00 (0.28) -0.527 0.072 ( -1.10, 0.05)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

631

Day 3

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 7

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

Day 5

Day 6

Day 8

149 -1.87 (0.29)

154 -2.03 (0.28) -0.162 0.590 ( -0.75, 0.43)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

146 -1.84 (0.29)

155 -2.24 (0.28) -0.399 0.189 ( -0.99, 0.20)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -1.98 (0.29)

151 -2.48 (0.28) -0.496 0.105 ( -1.10, 0.10)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -2.12 (0.32)

149 -2.52 (0.31) -0.399 0.218 ( -1.04, 0.24)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

632

Day 7

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 7

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28

Day 9

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 10

Day 12

149 -2.75 (0.28) -0.616 0.045 ( -1.22, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -2.17 (0.32)

148 -2.75 (0.31) -0.586 0.074 ( -1.23, 0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

143 -1.99 (0.32)

151 -2.86 (0.31) -0.872 0.008 ( -1.52, -0.23)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

144 -2.32 (0.31)

142 -3.06 (0.29) -0.735 0.023 ( -1.37, -0.10)

RM2008/00422/00

150 -2.13 (0.29)

CONFIDENTIAL

633

Day 11

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 7

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 13

Day 14

Day 16

149 -3.02 (0.31) -0.655 0.055 ( -1.33, 0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

145 -2.31 (0.32)

153 -3.42 (0.30) -1.109 0.001 ( -1.77, -0.45)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

143 -2.38 (0.34)

147 -3.31 (0.32) -0.925 0.009 ( -1.61, -0.24)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -2.60 (0.33)

150 -3.36 (0.32) -0.755 0.032 ( -1.44, -0.07)

RM2008/00422/00

145 -2.36 (0.32)

CONFIDENTIAL

634

Day 15

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 7

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 17

Day 18

Day 20

147 -3.19 (0.31) -0.694 0.046 ( -1.38, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

140 -2.60 (0.32)

152 -3.61 (0.30) -1.002 0.003 ( -1.67, -0.34)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

142 -2.77 (0.34)

145 -3.52 (0.33) -0.751 0.035 ( -1.45, -0.05)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -2.82 (0.34)

149 -3.83 (0.33) -1.009 0.005 ( -1.70, -0.31)

RM2008/00422/00

142 -2.50 (0.33)

CONFIDENTIAL

635

Day 19

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 7

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 21

Day 22

Day 24

148 -3.99 (0.31) -1.181 <0.001 ( -1.86, -0.50)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

142 -3.00 (0.34)

145 -3.94 (0.33) -0.935 0.009 ( -1.63, -0.24)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

133 -3.00 (0.34)

141 -3.76 (0.32) -0.764 0.037 ( -1.48, -0.05)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -3.03 (0.35)

143 -3.81 (0.33) -0.781 0.034 ( -1.50, -0.06)

RM2008/00422/00

142 -2.81 (0.33)

CONFIDENTIAL

636

Day 23

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 7

Table 7.84 Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 25

Day 26

Day 28

143 -3.97 (0.33) -1.258 <0.001 ( -1.99, -0.53)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

130 -2.71 (0.38)

137 -3.70 (0.37) -0.988 0.011 ( -1.75, -0.23)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

122 -2.82 (0.39)

124 -3.76 (0.38) -0.946 0.018 ( -1.73, -0.16)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

108 -3.36 (0.48)

113 -4.31 (0.47) -0.952 0.030 ( -1.81, -0.09)

RM2008/00422/00

134 -2.71 (0.36)

CONFIDENTIAL

637

Day 27

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 6

Table 7.85 Summary of Daily Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 9.1 (0.13) 9.1 (0.14) Median 9 8.9 Min - Max 6.0 - 12.0 3.5 - 12.0 153 -0.8 (0.14) -0.4 -6.0 - 3.6

159 8.5 (0.18) 8.5 2.0 - 12.0

159 -0.7 (0.11) -0.4 -7.4 - 2.9

Day 2 n Mean (Std Err) Median Min - Max

154 8.0 (0.18) 8 2.5 - 12.0

154 -1.1 (0.15) -0.9 -9.5 - 3.4

159 8.2 (0.18) 8 1.5 - 12.0

159 -0.9 (0.13) -0.9 -8.4 - 4.0

Day 3 n Mean (Std Err) Median Min - Max

154 7.9 (0.21) 8 2.0 - 12.0

154 -1.2 (0.18) -0.8 -9.5 - 4.1

160 7.4 (0.20) 7.5 1.0 - 12.0

160 -1.7 (0.16) -1.6 -9.4 - 3.6

Day 4 n Mean (Std Err) Median Min - Max

152 7.5 (0.21) 7.5 1.0 - 12.0

152 -1.6 (0.19) -1.3 -7.9 - 3.6

157 7.2 (0.22) 7.5 0.5 - 12.0

157 -1.9 (0.19) -1.6 -10.9 - 3.6

RM2008/00422/00

153 8.3 (0.19) 8.5 1.0 - 12.0

CONFIDENTIAL

638

Day 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 6

Table 7.85 Summary of Daily Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 5 n 149 149 158 158 Mean (Std Err) 7.2 (0.23) -1.9 (0.20) 7.1 (0.22) -2.1 (0.20) Median 7.5 -1.5 7.5 -1.6 Min - Max 0.0 - 12.0 -12.0 - 4.6 0.0 - 12.0 -10.9 - 3.3 151 -2.0 (0.21) -1.6 -11.5 - 4.6

157 6.8 (0.22) 7 0.0 - 12.0

157 -2.4 (0.19) -2.1 -11.9 - 4.3

Day 7 n Mean (Std Err) Median Min - Max

152 7.2 (0.23) 7.5 0.0 - 12.0

152 -2.0 (0.21) -1.5 -12.0 - 4.1

156 6.8 (0.23) 7 0.0 - 12.0

156 -2.4 (0.21) -2.2 -11.9 - 3.3

Day 8 n Mean (Std Err) Median Min - Max

151 7.1 (0.21) 7.5 0.5 - 12.0

151 -2.0 (0.21) -1.6 -9.0 - 5.1

154 6.5 (0.23) 7 0.0 - 12.0

154 -2.6 (0.21) -2.3 -11.4 - 2.1

Day 9 n Mean (Std Err) Median Min - Max

152 7.0 (0.22) 7 0.0 - 12.0

152 -2.1 (0.21) -1.7 -11.0 - 4.6

156 6.4 (0.24) 6.5 0.0 - 12.0

156 -2.8 (0.22) -2.4 -11.9 - 4.1

RM2008/00422/00

151 7.2 (0.23) 7 0.5 - 12.0

CONFIDENTIAL

639

Day 6 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 6

Table 7.85 Summary of Daily Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 10 n 151 151 156 156 Mean (Std Err) 6.9 (0.23) -2.2 (0.22) 6.4 (0.23) -2.8 (0.21) Median 7 -1.6 6.5 -2.5 Min - Max 0.0 - 12.0 -12.0 - 4.1 0.0 - 12.0 -11.4 - 3.1 150 -2.3 (0.23) -1.8 -11.5 - 4.6

157 6.1 (0.23) 6 0.0 - 12.0

157 -3.1 (0.21) -2.8 -11.9 - 3.6

Day 12 n Mean (Std Err) Median Min - Max

151 6.6 (0.23) 7 0.0 - 12.0

151 -2.4 (0.22) -2 -11.0 - 4.1

157 6.1 (0.24) 6 0.0 - 12.0

157 -3.1 (0.22) -2.9 -10.9 - 3.6

Day 13 n Mean (Std Err) Median Min - Max

151 6.6 (0.23) 7 0.0 - 12.0

151 -2.4 (0.23) -2 -11.5 - 4.6

156 6.2 (0.25) 6 0.0 - 12.0

156 -3.0 (0.24) -2.9 -11.3 - 4.0

Day 14 n Mean (Std Err) Median Min - Max

150 6.6 (0.24) 6.5 0.0 - 12.0

150 -2.5 (0.23) -1.9 -12.0 - 5.6

158 5.9 (0.25) 6 0.0 - 12.0

158 -3.2 (0.24) -2.9 -11.4 - 3.9

RM2008/00422/00

150 6.8 (0.24) 7 0.0 - 12.0

CONFIDENTIAL

640

Day 11 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 6

Table 7.85 Summary of Daily Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 15 n 147 147 156 156 Mean (Std Err) 6.7 (0.24) -2.3 (0.23) 5.8 (0.25) -3.4 (0.23) Median 7 -1.9 6 -3.3 Min - Max 0.0 - 12.0 -10.0 - 4.6 0.0 - 12.0 -11.4 - 3.0 150 -2.6 (0.24) -2.4 -10.0 - 5.6

156 5.8 (0.26) 6 0.0 - 12.0

156 -3.4 (0.25) -3.1 -12.0 - 2.9

Day 17 n Mean (Std Err) Median Min - Max

148 6.5 (0.24) 6.5 0.0 - 12.0

148 -2.6 (0.23) -2.2 -10.0 - 5.6

155 5.7 (0.26) 5.5 0.0 - 12.0

155 -3.4 (0.25) -3.4 -11.9 - 3.4

Day 18 n Mean (Std Err) Median Min - Max

147 6.5 (0.24) 7 0.0 - 12.0

147 -2.5 (0.24) -2.1 -12.0 - 4.6

156 5.5 (0.25) 5.5 0.0 - 12.0

156 -3.7 (0.24) -3.4 -12.0 - 2.9

Day 19 n Mean (Std Err) Median Min - Max

147 6.5 (0.26) 7 0.0 - 12.0

147 -2.6 (0.25) -2.3 -11.5 - 4.6

151 5.5 (0.26) 5.5 0.0 - 12.0

151 -3.7 (0.24) -3.6 -10.1 - 2.4

RM2008/00422/00

150 6.4 (0.24) 6.5 0.0 - 12.0

CONFIDENTIAL

641

Day 16 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 6

Table 7.85 Summary of Daily Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 20 n 145 145 155 155 Mean (Std Err) 6.3 (0.24) -2.7 (0.24) 5.4 (0.25) -3.8 (0.24) Median 6.5 -2.4 5 -3.5 Min - Max 0.0 - 12.0 -9.5 - 4.6 0.0 - 12.0 -12.0 - 2.4 146 -2.7 (0.25) -2.3 -12.0 - 5.6

156 5.2 (0.25) 5 0.0 - 12.0

156 -3.9 (0.24) -3.9 -12.0 - 2.9

Day 22 n Mean (Std Err) Median Min - Max

147 6.4 (0.25) 7 0.0 - 12.0

147 -2.7 (0.24) -2.3 -10.0 - 5.6

151 5.3 (0.25) 5.5 0.0 - 12.0

151 -3.9 (0.25) -3.8 -12.0 - 2.4

Day 23 n Mean (Std Err) Median Min - Max

146 6.1 (0.25) 6 0.0 - 12.0

146 -2.9 (0.24) -2.4 -10.0 - 5.6

149 5.4 (0.26) 5.5 0.0 - 12.0

149 -3.8 (0.26) -3.6 -12.0 - 3.4

Day 24 n Mean (Std Err) Median Min - Max

145 6.2 (0.26) 6.5 0.0 - 12.0

145 -2.9 (0.26) -2.5 -12.0 - 5.6

150 5.3 (0.26) 5.5 0.0 - 12.0

150 -3.9 (0.25) -3.9 -12.0 - 2.1

RM2008/00422/00

146 6.3 (0.25) 6.5 0.0 - 12.0

CONFIDENTIAL

642

Day 21 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 6

Table 7.85 Summary of Daily Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 25 n 139 139 149 149 Mean (Std Err) 6.1 (0.25) -2.9 (0.26) 5.1 (0.27) -4.2 (0.27) Median 6 -2.8 5 -4.1 Min - Max 0.0 - 12.0 -10.5 - 5.6 0.0 - 12.0 -12.0 - 2.4 133 6.1 (0.27) 6 0.0 - 12.0

133 -2.9 (0.27) -2.6 -11.5 - 5.6

144 5.2 (0.27) 5.5 0.0 - 12.0

144 -4.1 (0.26) -4 -12.0 - 2.1

Day 27 n Mean (Std Err) Median Min - Max

128 6.2 (0.27) 6.5 0.0 - 12.0

128 -3.0 (0.28) -2.5 -10.0 - 5.6

135 5.1 (0.28) 5.5 0.0 - 12.0

135 -4.2 (0.28) -4.3 -12.0 - 1.3

Day 28 n Mean (Std Err) Median Min - Max

113 5.9 (0.29) 6 0.0 - 12.0

113 -3.2 (0.29) -3 -10.5 - 3.9

115 5.4 (0.31) 5.5 0.0 - 12.0

115 -4.1 (0.30) -3.9 -11.4 - 1.6

CONFIDENTIAL

643

Day 26 n Mean (Std Err) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 7

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28

Day 1

Day 2

Day 4

153 -0.82 (0.17)

159 -0.69 (0.17) 0.130 0.469 ( -0.22, 0.48)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

154 -1.15 (0.19)

159 -0.96 (0.18) 0.183 0.356 ( -0.21, 0.57)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

154 -1.43 (0.23)

160 -1.84 (0.22) -0.416 0.082 ( -0.88, 0.05)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

152 -1.72 (0.26)

157 -2.00 (0.24) -0.281 0.291 ( -0.80, 0.24)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

644

Day 3

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 7

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28

Day 5

Day 6

Day 8

149 -1.88 (0.27)

158 -2.08 (0.26) -0.204 0.467 ( -0.76, 0.35)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.15 (0.27)

157 -2.50 (0.26) -0.355 0.203 ( -0.90, 0.19)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

152 -2.15 (0.28)

156 -2.58 (0.27) -0.430 0.136 ( -1.00, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.33 (0.28)

154 -2.93 (0.27) -0.595 0.036 ( -1.15, -0.04)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

645

Day 7

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 7

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28

Day 9

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 10

Day 12

156 -3.06 (0.27) -0.651 0.027 ( -1.23, -0.07)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.42 (0.29)

156 -2.98 (0.28) -0.567 0.055 ( -1.15, 0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

150 -2.40 (0.29)

157 -3.18 (0.28) -0.782 0.010 ( -1.37, -0.19)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -2.69 (0.29)

157 -3.26 (0.27) -0.579 0.053 ( -1.17, 0.01)

RM2008/00422/00

152 -2.41 (0.28)

CONFIDENTIAL

646

Day 11

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 7

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 13

Day 14

Day 16

156 -3.09 (0.29) -0.460 0.146 ( -1.08, 0.16)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

150 -2.57 (0.31)

158 -3.29 (0.29) -0.718 0.024 ( -1.34, -0.10)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -2.55 (0.31)

156 -3.60 (0.29) -1.051 <0.001 ( -1.67, -0.43)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

150 -2.87 (0.32)

156 -3.59 (0.30) -0.712 0.031 ( -1.36, -0.07)

RM2008/00422/00

151 -2.63 (0.31)

CONFIDENTIAL

647

Day 15

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 7

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 17

Day 18

Day 20

155 -3.69 (0.30) -0.812 0.013 ( -1.45, -0.17)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -2.79 (0.31)

156 -3.92 (0.29) -1.131 <0.001 ( -1.76, -0.50)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -2.92 (0.32)

151 -3.98 (0.31) -1.054 0.001 ( -1.70, -0.41)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

145 -2.84 (0.32)

155 -3.88 (0.30) -1.037 0.001 ( -1.67, -0.41)

RM2008/00422/00

148 -2.87 (0.31)

CONFIDENTIAL

648

Day 19

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 7

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 21

Day 22

Day 24

156 -4.22 (0.30) -1.145 <0.001 ( -1.79, -0.50)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -2.93 (0.32)

151 -4.16 (0.31) -1.230 <0.001 ( -1.88, -0.58)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

146 -3.33 (0.32)

149 -4.15 (0.30) -0.827 0.013 ( -1.48, -0.17)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

145 -3.32 (0.33)

150 -4.27 (0.31) -0.946 0.006 ( -1.62, -0.27)

RM2008/00422/00

146 -3.07 (0.32)

CONFIDENTIAL

649

Day 23

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 7

Table 7.86 Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 25

Day 26

Day 28

149 -4.34 (0.31) -1.175 <0.001 ( -1.86, -0.49)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

133 -3.13 (0.36)

144 -4.21 (0.35) -1.078 0.003 ( -1.78, -0.38)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

128 -3.09 (0.37)

135 -4.21 (0.35) -1.121 0.002 ( -1.84, -0.40)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

113 -3.64 (0.46)

115 -4.42 (0.44) -0.778 0.057 ( -1.58, 0.02)

RM2008/00422/00

139 -3.17 (0.34)

CONFIDENTIAL

650

Day 27

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 6

Table 7.87 Summary of AM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 9.1 (0.14) 9.1 (0.14) Median 9.3 9 Min - Max 5.3 - 12.0 3.5 - 12.0 150 -0.8 (0.16) -0.5 -7.0 - 5.3

159 8.4 (0.20) 8 0.0 - 12.0

159 -0.7 (0.12) -0.3 -6.0 - 2.5

Day 2 n Mean (Std Err) Median Min - Max

151 8.0 (0.19) 8 2.0 - 12.0

151 -1.1 (0.16) -1 -9.0 - 5.3

154 8.2 (0.19) 8 1.0 - 12.0

154 -1.0 (0.15) -0.8 -8.0 - 2.8

Day 3 n Mean (Std Err) Median Min - Max

147 8.0 (0.22) 8 2.0 - 12.0

147 -1.1 (0.19) -0.8 -9.0 - 4.3

155 7.5 (0.21) 8 1.0 - 12.0

155 -1.6 (0.17) -1.3 -9.8 - 3.8

Day 4 n Mean (Std Err) Median Min - Max

143 7.5 (0.23) 8 1.0 - 12.0

143 -1.6 (0.21) -1.3 -11.0 - 4.5

148 7.2 (0.23) 7.5 1.0 - 12.0

148 -1.9 (0.20) -1.5 -10.8 - 3.8

RM2008/00422/00

150 8.3 (0.20) 8 1.0 - 12.0

CONFIDENTIAL

651

Day 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 6

Table 7.87 Summary of AM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 5 n 149 149 154 154 Mean (Std Err) 7.2 (0.23) -1.8 (0.22) 7.1 (0.24) -2.0 (0.21) Median 7 -1.3 7 -1.5 Min - Max 0.0 - 12.0 -12.0 - 3.3 0.0 - 12.0 -10.8 - 3.3 146 -1.8 (0.21) -1.5 -12.0 - 3.0

155 6.8 (0.23) 7 0.0 - 12.0

155 -2.2 (0.19) -2 -11.8 - 4.3

Day 7 n Mean (Std Err) Median Min - Max

149 7.3 (0.23) 8 0.0 - 12.0

149 -1.8 (0.22) -1.3 -12.0 - 4.0

151 6.7 (0.24) 7 0.0 - 12.0

151 -2.4 (0.22) -2.3 -11.8 - 3.3

Day 8 n Mean (Std Err) Median Min - Max

148 7.2 (0.22) 7 1.0 - 12.0

148 -1.9 (0.21) -1.5 -8.0 - 4.0

149 6.5 (0.24) 7 0.0 - 12.0

149 -2.6 (0.21) -2.3 -11.8 - 3.3

Day 9 n Mean (Std Err) Median Min - Max

150 7.0 (0.22) 7 0.0 - 12.0

150 -2.1 (0.22) -1.5 -10.0 - 4.0

149 6.4 (0.26) 6 0.0 - 12.0

149 -2.7 (0.23) -2.3 -11.8 - 2.8

RM2008/00422/00

146 7.3 (0.23) 8 0.0 - 12.0

CONFIDENTIAL

652

Day 6 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 6

Table 7.87 Summary of AM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 10 n 147 147 148 148 Mean (Std Err) 6.9 (0.24) -2.2 (0.23) 6.2 (0.25) -2.9 (0.23) Median 7 -2 6 -2.5 Min - Max 0.0 - 12.0 -12.0 - 2.5 0.0 - 12.0 -11.8 - 3.3 143 -2.2 (0.23) -2 -11.0 - 4.0

151 6.0 (0.25) 6 0.0 - 12.0

151 -3.1 (0.22) -3 -11.8 - 3.3

Day 12 n Mean (Std Err) Median Min - Max

144 6.6 (0.24) 7 0.0 - 12.0

144 -2.4 (0.23) -2 -11.0 - 3.3

142 6.2 (0.25) 6 0.0 - 12.0

142 -3.0 (0.23) -2.8 -10.0 - 3.3

Day 13 n Mean (Std Err) Median Min - Max

145 6.7 (0.25) 7 0.0 - 12.0

145 -2.3 (0.24) -2 -12.0 - 4.3

149 6.1 (0.26) 6 0.0 - 12.0

149 -3.0 (0.24) -3 -11.0 - 4.0

Day 14 n Mean (Std Err) Median Min - Max

145 6.6 (0.25) 7 0.0 - 12.0

145 -2.4 (0.23) -2 -12.0 - 4.5

153 5.8 (0.25) 6 0.0 - 12.0

153 -3.3 (0.24) -3 -11.8 - 3.5

RM2008/00422/00

143 6.9 (0.25) 7 0.0 - 12.0

CONFIDENTIAL

653

Day 11 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 6

Table 7.87 Summary of AM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 15 n 143 143 147 147 Mean (Std Err) 6.7 (0.26) -2.4 (0.25) 5.7 (0.26) -3.4 (0.25) Median 7 -2 6 -3.3 Min - Max 0.0 - 12.0 -12.0 - 4.5 0.0 - 12.0 -11.8 - 3.0 141 -2.5 (0.24) -2 -11.0 - 4.5

150 5.7 (0.27) 6 0.0 - 12.0

150 -3.4 (0.25) -3.4 -12.0 - 2.3

Day 17 n Mean (Std Err) Median Min - Max

142 6.5 (0.25) 7 0.0 - 12.0

142 -2.6 (0.24) -2.1 -10.0 - 4.5

147 5.8 (0.27) 6 0.0 - 12.0

147 -3.3 (0.26) -3 -11.8 - 4.0

Day 18 n Mean (Std Err) Median Min - Max

140 6.5 (0.25) 7 0.0 - 12.0

140 -2.5 (0.24) -2 -12.0 - 2.8

152 5.4 (0.25) 5 0.0 - 12.0

152 -3.7 (0.24) -3.6 -12.0 - 2.5

Day 19 n Mean (Std Err) Median Min - Max

142 6.4 (0.26) 7 0.0 - 12.0

142 -2.6 (0.25) -2.3 -12.0 - 2.8

145 5.5 (0.27) 5 0.0 - 12.0

145 -3.7 (0.25) -3.8 -10.3 - 2.5

RM2008/00422/00

141 6.5 (0.25) 7 0.0 - 12.0

CONFIDENTIAL

654

Day 16 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 6

Table 7.87 Summary of AM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 20 n 141 141 149 149 Mean (Std Err) 6.3 (0.26) -2.8 (0.26) 5.3 (0.26) -3.8 (0.25) Median 7 -2.8 5 -3.8 Min - Max 0.0 - 12.0 -12.0 - 3.3 0.0 - 12.0 -12.0 - 2.5 142 -2.6 (0.25) -2 -12.0 - 4.5

148 5.0 (0.26) 5 0.0 - 12.0

148 -4.1 (0.25) -4 -12.0 - 3.5

Day 22 n Mean (Std Err) Median Min - Max

142 6.4 (0.26) 7 0.0 - 12.0

142 -2.6 (0.26) -2 -12.0 - 4.5

145 5.3 (0.27) 5 0.0 - 12.0

145 -4.0 (0.26) -3.8 -12.0 - 2.5

Day 23 n Mean (Std Err) Median Min - Max

133 6.2 (0.26) 6 0.0 - 12.0

133 -2.9 (0.25) -2.7 -9.0 - 4.5

141 5.4 (0.28) 5 0.0 - 12.0

141 -3.8 (0.28) -3.5 -12.0 - 4.0

Day 24 n Mean (Std Err) Median Min - Max

141 6.1 (0.26) 6 0.0 - 12.0

141 -3.0 (0.26) -2.5 -12.0 - 4.5

143 5.3 (0.27) 5 0.0 - 12.0

143 -3.9 (0.27) -4 -12.0 - 3.3

RM2008/00422/00

142 6.4 (0.26) 6.5 0.0 - 12.0

CONFIDENTIAL

655

Day 21 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 6

Table 7.87 Summary of AM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 25 n 134 134 143 143 Mean (Std Err) 6.2 (0.26) -2.8 (0.25) 5.1 (0.29) -4.1 (0.29) Median 6.5 -2.6 5 -4 Min - Max 0.0 - 12.0 -10.0 - 4.5 0.0 - 12.0 -12.0 - 3.3 130 6.1 (0.28) 6 0.0 - 12.0

130 -3.0 (0.27) -2.9 -12.0 - 4.5

137 5.1 (0.28) 5 0.0 - 12.0

137 -4.2 (0.27) -4 -12.0 - 2.3

Day 27 n Mean (Std Err) Median Min - Max

122 6.3 (0.29) 6 0.0 - 12.0

122 -2.8 (0.29) -2.5 -12.0 - 5.3

124 5.3 (0.29) 5.5 0.0 - 12.0

124 -4.1 (0.29) -4 -12.0 - 1.8

Day 28 n Mean (Std Err) Median Min - Max

108 5.9 (0.31) 6 0.0 - 12.0

108 -3.1 (0.30) -3 -10.3 - 5.3

113 5.4 (0.32) 6 0.0 - 12.0

113 -4.1 (0.31) -3.8 -11.8 - 1.8

CONFIDENTIAL

656

Day 26 n Mean (Std Err) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 7

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28

Day 1

Day 2

Day 4

150 -0.92 (0.20)

159 -0.72 (0.19) 0.196 0.334 ( -0.20, 0.59)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -1.15 (0.21)

154 -1.00 (0.20) 0.148 0.496 ( -0.28, 0.58)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -1.17 (0.24)

155 -1.70 (0.23) -0.532 0.037 ( -1.03, -0.03)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

143 -1.65 (0.28)

148 -1.93 (0.27) -0.278 0.330 ( -0.84, 0.28)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

657

Day 3

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 7

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28

Day 5

Day 6

Day 8

149 -1.96 (0.29)

154 -2.09 (0.27) -0.127 0.671 ( -0.71, 0.46)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

146 -1.92 (0.27)

155 -2.34 (0.26) -0.418 0.139 ( -0.97, 0.14)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -2.01 (0.29)

151 -2.53 (0.28) -0.520 0.089 ( -1.12, 0.08)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -2.18 (0.28)

149 -2.84 (0.28) -0.664 0.021 ( -1.23, -0.10)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

658

Day 7

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 7

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28

Day 9

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 10

Day 12

149 -2.99 (0.28) -0.611 0.046 ( -1.21, -0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

147 -2.27 (0.31)

148 -3.00 (0.30) -0.726 0.020 ( -1.34, -0.11)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

143 -2.22 (0.30)

151 -3.11 (0.29) -0.893 0.004 ( -1.50, -0.28)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

144 -2.70 (0.30)

142 -3.24 (0.28) -0.543 0.081 ( -1.15, 0.07)

RM2008/00422/00

150 -2.38 (0.29)

CONFIDENTIAL

659

Day 11

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 7

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 13

Day 14

Day 16

149 -3.20 (0.31) -0.745 0.026 ( -1.40, -0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

145 -2.49 (0.31)

153 -3.37 (0.29) -0.883 0.006 ( -1.52, -0.25)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

143 -2.41 (0.33)

147 -3.46 (0.31) -1.058 0.002 ( -1.72, -0.40)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -2.80 (0.32)

150 -3.69 (0.31) -0.887 0.009 ( -1.55, -0.22)

RM2008/00422/00

145 -2.45 (0.32)

CONFIDENTIAL

660

Day 15

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 7

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 17

Day 18

Day 20

147 -3.53 (0.31) -0.748 0.027 ( -1.41, -0.08)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

140 -2.74 (0.31)

152 -3.91 (0.29) -1.170 <0.001 ( -1.80, -0.54)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

142 -2.86 (0.33)

145 -3.91 (0.31) -1.054 0.002 ( -1.72, -0.39)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -2.92 (0.33)

149 -3.98 (0.32) -1.055 0.002 ( -1.73, -0.38)

RM2008/00422/00

142 -2.79 (0.33)

CONFIDENTIAL

661

Day 19

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 7

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 21

Day 22

Day 24

148 -4.47 (0.30) -1.403 <0.001 ( -2.06, -0.74)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

142 -2.88 (0.33)

145 -4.15 (0.33) -1.270 <0.001 ( -1.96, -0.58)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

133 -3.27 (0.34)

141 -4.19 (0.32) -0.918 0.010 ( -1.62, -0.22)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -3.25 (0.34)

143 -4.11 (0.32) -0.862 0.014 ( -1.55, -0.17)

RM2008/00422/00

142 -3.07 (0.33)

CONFIDENTIAL

662

Day 23

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 7

Table 7.88 Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 25

Day 26

Day 28

143 -4.24 (0.33) -1.226 <0.001 ( -1.94, -0.51)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

130 -3.19 (0.37)

137 -4.25 (0.36) -1.065 0.004 ( -1.79, -0.34)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

122 -2.97 (0.37)

124 -4.17 (0.36) -1.195 0.002 ( -1.95, -0.44)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

108 -3.51 (0.48)

113 -4.32 (0.46) -0.808 0.058 ( -1.64, 0.03)

RM2008/00422/00

134 -3.02 (0.35)

CONFIDENTIAL

663

Day 27

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 6

Table 7.89 Summary of PM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 9.1 (0.13) 9.2 (0.14) Median 9 9 Min - Max 5.3 - 12.0 3.5 - 12.0 145 -0.7 (0.16) -0.3 -6.0 - 5.8

155 8.5 (0.19) 8 3.0 - 12.0

155 -0.6 (0.14) -0.5 -8.7 - 3.5

Day 2 n Mean (Std Err) Median Min - Max

151 8.0 (0.20) 8 2.0 - 12.0

151 -1.1 (0.17) -0.8 -10.0 - 4.0

155 8.2 (0.19) 8 2.0 - 12.0

155 -1.0 (0.15) -0.5 -8.7 - 4.0

Day 3 n Mean (Std Err) Median Min - Max

143 7.6 (0.22) 8 2.0 - 12.0

143 -1.4 (0.21) -1 -10.0 - 4.8

155 7.4 (0.21) 8 1.0 - 12.0

155 -1.8 (0.18) -1.8 -9.7 - 4.0

Day 4 n Mean (Std Err) Median Min - Max

148 7.4 (0.23) 8 1.0 - 12.0

148 -1.7 (0.21) -1.4 -8.0 - 6.8

151 7.3 (0.23) 8 0.0 - 12.0

151 -1.9 (0.21) -1.7 -11.0 - 3.5

RM2008/00422/00

145 8.4 (0.20) 8 3.0 - 12.0

CONFIDENTIAL

664

Day 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 6

Table 7.89 Summary of PM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 5 n 144 144 150 150 Mean (Std Err) 7.2 (0.24) -1.9 (0.23) 6.9 (0.23) -2.3 (0.22) Median 7 -1.8 7 -1.9 Min - Max 0.0 - 12.0 -12.0 - 6.8 0.0 - 12.0 -11.0 - 3.3 141 -2.2 (0.24) -2 -11.0 - 6.8

149 6.7 (0.24) 7 0.0 - 12.0

149 -2.5 (0.22) -2.5 -12.0 - 4.3

Day 7 n Mean (Std Err) Median Min - Max

149 7.0 (0.25) 8 0.0 - 12.0

149 -2.1 (0.24) -1.8 -12.0 - 6.8

151 6.7 (0.24) 7 0.0 - 12.0

151 -2.6 (0.23) -2.5 -12.0 - 3.3

Day 8 n Mean (Std Err) Median Min - Max

144 7.0 (0.23) 7 0.0 - 12.0

144 -2.1 (0.23) -2 -10.0 - 6.8

149 6.5 (0.24) 7 0.0 - 12.0

149 -2.7 (0.22) -2.3 -11.0 - 3.0

Day 9 n Mean (Std Err) Median Min - Max

145 7.0 (0.24) 7 0.0 - 12.0

145 -2.1 (0.24) -1.8 -12.0 - 6.8

151 6.3 (0.25) 7 0.0 - 12.0

151 -2.9 (0.23) -2.8 -12.0 - 4.0

RM2008/00422/00

141 6.9 (0.26) 7 0.0 - 12.0

CONFIDENTIAL

665

Day 6 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 6

Table 7.89 Summary of PM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 10 n 142 142 150 150 Mean (Std Err) 6.9 (0.25) -2.1 (0.25) 6.4 (0.24) -2.8 (0.22) Median 7 -1.8 6 -2.6 Min - Max 0.0 - 12.0 -12.0 - 5.8 0.0 - 12.0 -11.0 - 3.0 144 -2.3 (0.26) -1.7 -12.0 - 5.8

150 6.1 (0.25) 6 0.0 - 12.0

150 -3.2 (0.23) -3 -12.0 - 4.0

Day 12 n Mean (Std Err) Median Min - Max

146 6.6 (0.25) 7 0.0 - 12.0

146 -2.4 (0.25) -2.3 -11.0 - 5.8

150 6.0 (0.26) 6 0.0 - 12.0

150 -3.2 (0.24) -3 -11.0 - 4.0

Day 13 n Mean (Std Err) Median Min - Max

145 6.5 (0.26) 7 0.0 - 12.0

145 -2.6 (0.25) -2.3 -11.0 - 6.8

149 6.3 (0.26) 6 0.0 - 12.0

149 -3.0 (0.25) -3 -12.0 - 5.0

Day 14 n Mean (Std Err) Median Min - Max

141 6.6 (0.25) 7 0.0 - 12.0

141 -2.4 (0.24) -2 -12.0 - 6.8

153 6.0 (0.27) 6 0.0 - 12.0

153 -3.3 (0.25) -3 -11.3 - 4.5

RM2008/00422/00

144 6.8 (0.26) 7 0.0 - 12.0

CONFIDENTIAL

666

Day 11 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 6

Table 7.89 Summary of PM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 15 n 140 140 151 151 Mean (Std Err) 6.8 (0.25) -2.3 (0.25) 5.7 (0.26) -3.5 (0.25) Median 7 -1.8 5 -3.3 Min - Max 0.0 - 12.0 -10.0 - 5.0 0.0 - 12.0 -11.3 - 4.0 139 -2.7 (0.26) -2.3 -10.0 - 6.8

151 5.8 (0.27) 6 0.0 - 12.0

151 -3.4 (0.26) -3.3 -12.0 - 4.0

Day 17 n Mean (Std Err) Median Min - Max

137 6.5 (0.27) 7 0.0 - 12.0

137 -2.6 (0.26) -2 -11.0 - 6.8

141 5.7 (0.28) 6 0.0 - 12.0

141 -3.5 (0.28) -3.3 -12.0 - 3.5

Day 18 n Mean (Std Err) Median Min - Max

137 6.5 (0.27) 7 0.0 - 12.0

137 -2.6 (0.27) -2.3 -12.0 - 6.8

148 5.6 (0.27) 5 0.0 - 12.0

148 -3.6 (0.26) -3.3 -10.3 - 3.5

Day 19 n Mean (Std Err) Median Min - Max

139 6.5 (0.28) 7 0.0 - 12.0

139 -2.6 (0.29) -2.5 -11.0 - 6.8

144 5.5 (0.27) 6 0.0 - 12.0

144 -3.7 (0.26) -3.9 -10.0 - 2.3

RM2008/00422/00

139 6.2 (0.26) 6 0.0 - 12.0

CONFIDENTIAL

667

Day 16 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 6

Table 7.89 Summary of PM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 20 n 138 138 149 149 Mean (Std Err) 6.4 (0.25) -2.6 (0.26) 5.4 (0.27) -3.8 (0.25) Median 6 -2.3 6 -3.5 Min - Max 0.0 - 12.0 -10.0 - 6.8 0.0 - 12.0 -12.0 - 2.3 135 -2.7 (0.28) -2 -12.0 - 6.8

148 5.3 (0.27) 5 0.0 - 12.0

148 -4.0 (0.25) -4 -12.0 - 2.3

Day 22 n Mean (Std Err) Median Min - Max

138 6.4 (0.26) 7 0.0 - 12.0

138 -2.6 (0.26) -2 -10.8 - 6.8

146 5.4 (0.27) 5.5 0.0 - 12.0

146 -4.0 (0.26) -4 -12.0 - 2.8

Day 23 n Mean (Std Err) Median Min - Max

141 6.1 (0.26) 6 0.0 - 12.0

141 -2.9 (0.27) -2.5 -11.0 - 6.8

143 5.5 (0.28) 6 0.0 - 12.0

143 -3.8 (0.27) -3.8 -12.0 - 3.8

Day 24 n Mean (Std Err) Median Min - Max

130 6.3 (0.29) 7 0.0 - 12.0

130 -2.8 (0.30) -2.3 -12.0 - 6.8

140 5.4 (0.29) 6 0.0 - 12.0

140 -4.0 (0.27) -4 -12.0 - 3.8

RM2008/00422/00

135 6.3 (0.27) 7 0.0 - 12.0

CONFIDENTIAL

668

Day 21 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 6

Table 7.89 Summary of PM Reflective Total Nasal Symptom Scores Days 1-28

__________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Day 25 n 130 130 141 141 Mean (Std Err) 6.0 (0.29) -3.0 (0.30) 5.1 (0.28) -4.2 (0.28) Median 6 -2.6 5 -4 Min - Max 0.0 - 12.0 -11.0 - 6.8 0.0 - 12.0 -12.0 - 2.5 126 6.3 (0.29) 7 0.0 - 12.0

126 -2.8 (0.30) -2.5 -11.0 - 6.8

137 5.1 (0.28) 5 0.0 - 12.0

137 -4.2 (0.27) -4.3 -12.0 - 2.3

Day 27 n Mean (Std Err) Median Min - Max

122 6.0 (0.29) 6 0.0 - 12.0

122 -3.0 (0.30) -2.8 -10.5 - 6.8

130 5.1 (0.29) 5.5 0.0 - 12.0

130 -4.3 (0.29) -4 -12.0 - 2.3

Day 28 n Mean (Std Err) Median Min - Max

105 5.9 (0.31) 6 0.0 - 12.0

105 -3.1 (0.31) -2.8 -12.0 - 2.8

110 5.4 (0.32) 6 0.0 - 12.0

110 -4.2 (0.32) -4 -11.5 - 2.3

CONFIDENTIAL

669

Day 26 n Mean (Std Err) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 7

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28

Day 1

Day 2

Day 4

145 -0.71 (0.20)

155 -0.66 (0.19) 0.051 0.807 ( -0.36, 0.46)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

151 -1.23 (0.22)

155 -1.05 (0.21) 0.183 0.420 ( -0.26, 0.63)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

143 -1.71 (0.25)

155 -1.97 (0.24) -0.252 0.348 ( -0.78, 0.28)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

148 -1.86 (0.28)

151 -2.00 (0.27) -0.140 0.628 ( -0.71, 0.43)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

670

Day 3

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 7

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28

Day 5

Day 6

Day 8

144 -1.81 (0.30)

150 -2.15 (0.29) -0.343 0.265 ( -0.95, 0.26)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -2.47 (0.31)

149 -2.70 (0.29) -0.228 0.468 ( -0.85, 0.39)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

149 -2.34 (0.30)

151 -2.70 (0.29) -0.362 0.250 ( -0.98, 0.26)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

144 -2.45 (0.29)

149 -2.98 (0.28) -0.534 0.081 ( -1.13, 0.07)

RM2008/00422/00

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

CONFIDENTIAL

671

Day 7

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 7

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28

Day 9

________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 10

Day 12

151 -3.17 (0.30) -0.690 0.031 ( -1.32, -0.06)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

142 -2.42 (0.31)

150 -3.03 (0.30) -0.619 0.053 ( -1.25, 0.01)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

144 -2.55 (0.32)

150 -3.35 (0.30) -0.804 0.015 ( -1.45, -0.16)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

146 -2.69 (0.32)

150 -3.33 (0.30) -0.638 0.056 ( -1.29, 0.02)

RM2008/00422/00

145 -2.48 (0.31)

CONFIDENTIAL

672

Day 11

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 7

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 13

Day 14

Day 16

149 -3.11 (0.32) -0.290 0.397 ( -0.96, 0.38)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -2.57 (0.33)

153 -3.28 (0.31) -0.715 0.036 ( -1.38, -0.05)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

140 -2.57 (0.33)

151 -3.74 (0.31) -1.167 <0.001 ( -1.82, -0.51)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

139 -2.92 (0.35)

151 -3.52 (0.33) -0.595 0.100 ( -1.30, 0.11)

RM2008/00422/00

145 -2.82 (0.33)

CONFIDENTIAL

673

Day 15

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 7

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 17

Day 18

Day 20

141 -3.79 (0.34) -0.916 0.014 ( -1.64, -0.19)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

137 -2.87 (0.35)

148 -3.85 (0.34) -0.978 0.007 ( -1.68, -0.27)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

139 -2.97 (0.36)

144 -4.07 (0.34) -1.104 0.003 ( -1.82, -0.39)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

138 -2.75 (0.34)

149 -3.86 (0.32) -1.116 0.001 ( -1.79, -0.44)

RM2008/00422/00

137 -2.88 (0.35)

CONFIDENTIAL

674

Day 19

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 7

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 21

Day 22

Day 24

148 -3.95 (0.33) -1.162 0.001 ( -1.86, -0.47)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

138 -3.04 (0.34)

146 -4.26 (0.33) -1.219 <0.001 ( -1.92, -0.52)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

141 -3.27 (0.34)

143 -4.04 (0.32) -0.769 0.027 ( -1.45, -0.09)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

130 -3.16 (0.36)

140 -4.31 (0.34) -1.149 0.002 ( -1.89, -0.41)

RM2008/00422/00

135 -2.79 (0.35)

CONFIDENTIAL

675

Day 23

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 7

Table 7.90 Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores Days 1-28 ________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) ----------------------------------------------------------------

Day 25

Day 26

Day 28

141 -4.52 (0.34) -1.062 0.004 ( -1.79, -0.34)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

126 -2.95 (0.38)

137 -4.29 (0.36) -1.344 <0.001 ( -2.09, -0.60)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

122 -3.10 (0.38)

130 -4.13 (0.36) -1.033 0.007 ( -1.79, -0.28)

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

105 -3.67 (0.49)

110 -4.48 (0.47) -0.811 0.065 ( -1.67, 0.05)

RM2008/00422/00

130 -3.46 (0.36)

CONFIDENTIAL

676

Day 27

n LS Mean (Std Err) LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: ITT/Age 12 - <18 years

Page 1 of 2

Table 7.91 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=9) (N=9) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 9 9 Mean (Std Err) 9.4 (0.53) 9.2 (0.51) Median 9 9.9 Min - Max 7.3 - 12.0 6.9 - 11.8 9 -1.6 (0.62) -0.9 -5.3 - 0.2

9 7.5 (0.79) 8 4.4 - 10.8

9 -1.7 (0.67) -1.5 -5.4 - 0.6

Week 2 n Mean (Std Err) Median Min - Max

8 6.9 (1.10) 7.5 0.4 - 9.9

8 -2.2 (1.06) -1.1 -7.9 - 1.2

9 6.5 (0.81) 6.7 3.7 - 10.8

9 -2.7 (0.85) -3.4 -5.8 - 0.9

Week 3 n Mean (Std Err) Median Min - Max

8 7.1 (1.14) 7.6 0.4 - 11.3

8 -2.0 (1.08) -1.4 -7.8 - 0.9

9 6.3 (0.93) 6.6 3.0 - 11.1

9 -2.9 (0.94) -3.9 -6.7 - 1.2

Week 4 n Mean (Std Err) Median Min - Max

8 7.3 (1.12) 7.9 0.1 - 10.2

8 -1.7 (1.13) -1 -8.2 - 2.9

9 5.0 (1.30) 5.1 0.0 - 11.4

9 -4.2 (1.30) -5.1 -9.9 - 1.5

RM2008/00422/00

9 7.8 (0.84) 8.1 3.0 - 11.9

CONFIDENTIAL

677

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Age 12 - <18 years

Page 2 of 2

Table 7.91 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=9) (N=9) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 9 9 9 9 Mean (Std Err) 7.7 (1.02) -1.7 (0.86) 6.4 (0.90) -2.8 (0.89) Median 8 -1 6.8 -3.4 Min - Max 1.0 - 11.9 -7.3 - 0.7 3.3 - 10.8 -6.6 - 0.9

CONFIDENTIAL

678

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Age 18

-

Page 1 of 2

<65 years

Table 7.92 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=141) (N=146) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 141 146 Mean (Std Err) 9.1 (0.13) 9.1 (0.15) Median 8.9 8.9 Min - Max 6.0 - 12.0 3.5 - 12.0 141 -1.5 (0.17) -1.2 -9.6 - 3.9

146 7.4 (0.19) 7.5 0.9 - 12.0

146 -1.7 (0.16) -1.6 -8.9 - 2.2

Week 2 n Mean (Std Err) Median Min - Max

140 6.7 (0.22) 6.9 0.9 - 12.0

140 -2.3 (0.21) -1.9 -11.1 - 4.7

144 6.3 (0.24) 6.4 0.4 - 12.0

144 -2.9 (0.22) -2.5 -11.4 - 2.6

Week 3 n Mean (Std Err) Median Min - Max

139 6.4 (0.24) 6.4 0.0 - 12.0

139 -2.7 (0.23) -2.3 -9.8 - 5.1

142 5.6 (0.25) 5.5 0.0 - 12.0

142 -3.6 (0.24) -3.3 -11.1 - 2.2

Week 4 n Mean (Std Err) Median Min - Max

137 6.1 (0.25) 6 0.0 - 12.0

137 -3.0 (0.25) -2.6 -9.9 - 5.6

139 5.3 (0.26) 5.5 0.0 - 12.0

139 -4.0 (0.25) -3.8 -12.0 - 2.0

RM2008/00422/00

141 7.6 (0.20) 7.7 2.1 - 12.0

CONFIDENTIAL

679

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Age 18

-

<65 years

Page 2 of 2

Table 7.92 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=141) (N=146) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 141 141 146 146 Mean (Std Err) 6.8 (0.21) -2.3 (0.20) 6.1 (0.22) -3.0 (0.20) Median 6.8 -1.8 6.2 -2.8 Min - Max 1.3 - 12.0 -10.1 - 4.8 0.9 - 12.0 -10.5 - 1.0

CONFIDENTIAL

680

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Age >=65 years

Page 1 of 2

Table 7.93 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=5) (N=5) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 5 5 Mean (Std Err) 9.5 (0.83) 9.1 (1.00) Median 10.3 8.9 Min - Max 6.8 - 11.0 6.9 - 11.8 5 -1.0 (0.46) -0.8 -2.2 - 0.4

5 7.5 (1.04) 6.5 4.8 - 10.5

5 -1.6 (0.44) -2.1 -2.5 - -0.5

Week 2 n Mean (Std Err) Median Min - Max

5 8.2 (0.69) 8.5 5.9 - 10.1

5 -1.3 (0.50) -0.9 -2.5 - 0.2

5 5.5 (0.90) 5.6 2.9 - 8.4

5 -3.6 (0.73) -3.9 -5.7 - -1.4

Week 3 n Mean (Std Err) Median Min - Max

4 8.4 (0.85) 8.3 6.4 - 10.5

4 -0.8 (0.48) -0.4 -2.2 - 0.0

5 4.5 (1.26) 3.7 0.9 - 7.8

5 -4.6 (0.59) -4.9 -6.0 - -3.2

Week 4 n Mean (Std Err) Median Min - Max

4 7.3 (0.96) 7.9 4.6 - 9.0

4 -1.8 (0.32) -2.1 -2.2 - -0.8

5 3.2 (1.46) 1.6 0.1 - 7.2

5 -5.9 (0.82) -5.6 -8.8 - -3.8

RM2008/00422/00

5 8.5 (0.75) 8.9 5.9 - 10.4

CONFIDENTIAL

681

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Age >=65 years

Page 2 of 2

Table 7.93 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=5) (N=5) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 5 5 5 5 Mean (Std Err) 8.3 (0.71) -1.2 (0.40) 5.2 (1.13) -3.9 (0.56) Median 8.6 -1.1 4.3 -4.5 Min - Max 5.7 - 9.9 -2.2 - 0.1 2.4 - 8.5 -5.3 - -2.5

CONFIDENTIAL

682

RM2008/00422/00

Protocol: FFU111439 Population: ITT/USA

Page 1 of 2 Table 7.94 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=56) (N=58) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 56 58 Mean (Std Err) 9.2 (0.22) 9.6 (0.22) Median 9.2 9.4 Min - Max 6.0 - 12.0 6.3 - 12.0 56 -1.4 (0.22) -1 -5.5 - 1.7

58 8.0 (0.30) 8.2 2.9 - 12.0

58 -1.6 (0.27) -1.3 -8.9 - 2.2

Week 2 n Mean (Std Err) Median Min - Max

55 7.1 (0.35) 7.4 1.8 - 11.7

55 -2.0 (0.27) -1.8 -6.3 - 1.0

58 7.1 (0.36) 7 0.5 - 12.0

58 -2.4 (0.36) -2.1 -11.4 - 2.6

Week 3 n Mean (Std Err) Median Min - Max

54 6.9 (0.40) 6.9 1.6 - 11.6

54 -2.2 (0.33) -1.9 -7.2 - 2.4

58 6.5 (0.37) 6.6 0.8 - 12.0

58 -3.1 (0.38) -2.8 -11.1 - 1.2

Week 4 n Mean (Std Err) Median Min - Max

54 6.8 (0.41) 7 1.3 - 11.7

54 -2.3 (0.36) -2 -8.3 - 2.9

57 6.2 (0.37) 6.1 1.1 - 12.0

57 -3.4 (0.39) -3.2 -10.7 - 1.5

RM2008/00422/00

56 7.8 (0.34) 8.1 2.7 - 11.9

CONFIDENTIAL

683

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/USA

Page 2 of 2 Table 7.94 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=56) (N=58) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 56 56 58 58 Mean (Std Err) 7.3 (0.35) -1.9 (0.26) 7.0 (0.32) -2.6 (0.33) Median 7.6 -1.7 7.1 -2.5 Min - Max 2.2 - 11.9 -5.9 - 1.3 1.3 - 12.0 -10.5 - 1.0

CONFIDENTIAL

684

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Canada

Page 1 of 2 Table 7.95 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=35) (N=35) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 35 35 Mean (Std Err) 9.4 (0.25) 9.1 (0.31) Median 9.3 9 Min - Max 6.9 - 12.0 4.5 - 12.0 35 -1.2 (0.35) -0.9 -7.6 - 1.5

35 7.6 (0.45) 7.9 0.9 - 12.0

35 -1.5 (0.30) -1.4 -7.0 - 0.7

Week 2 n Mean (Std Err) Median Min - Max

35 7.2 (0.41) 7.6 0.4 - 12.0

35 -2.2 (0.44) -1.8 -8.4 - 2.6

33 6.4 (0.50) 6.4 0.4 - 11.6

33 -3.0 (0.42) -2.5 -8.5 - 2.2

Week 3 n Mean (Std Err) Median Min - Max

35 6.9 (0.43) 7.5 0.4 - 12.0

35 -2.5 (0.48) -2.2 -8.1 - 2.1

33 5.4 (0.54) 5.4 0.0 - 11.5

33 -3.9 (0.48) -3.9 -8.2 - 0.5

Week 4 n Mean (Std Err) Median Min - Max

33 6.6 (0.44) 7.2 0.1 - 11.7

33 -2.8 (0.48) -2.4 -8.9 - 1.8

32 5.3 (0.57) 5.3 0.4 - 11.8

32 -4.1 (0.52) -3.7 -10.0 - 0.8

RM2008/00422/00

35 8.1 (0.38) 8.6 3.0 - 11.4

CONFIDENTIAL

685

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Canada

Page 2 of 2 Table 7.95 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=35) (N=35) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 35 35 35 35 Mean (Std Err) 7.2 (0.38) -2.1 (0.41) 6.1 (0.47) -3.0 (0.38) Median 7.9 -1.7 6.2 -3 Min - Max 1.0 - 11.8 -8.0 - 1.9 0.9 - 11.6 -8.4 - 0.6

CONFIDENTIAL

686

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Estonia

Page 1 of 2 Table 7.96 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=9) (N=8) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 9 8 Mean (Std Err) 8.9 (0.57) 8.6 (0.58) Median 8.9 8 Min - Max 6.4 - 12.0 6.8 - 11.1 9 -0.4 (0.61) -0.6 -2.8 - 3.9

8 7.1 (0.88) 6.8 3.9 - 10.6

8 -1.5 (0.66) -2.1 -3.8 - 1.9

Week 2 n Mean (Std Err) Median Min - Max

9 8.0 (0.91) 8.1 3.8 - 12.0

9 -0.9 (0.90) -1.1 -5.8 - 4.7

8 6.0 (0.93) 5.9 2.9 - 10.5

8 -2.6 (0.62) -3.2 -4.8 - 0.4

Week 3 n Mean (Std Err) Median Min - Max

9 7.6 (0.98) 7.9 2.6 - 12.0

9 -1.3 (1.02) -1.6 -6.9 - 5.1

8 4.8 (0.86) 4.1 1.7 - 8.2

8 -3.7 (0.42) -3.6 -6.0 - -2.0

Week 4 n Mean (Std Err) Median Min - Max

9 7.5 (1.02) 7 2.9 - 12.0

9 -1.4 (1.08) -1.5 -6.6 - 5.6

8 4.8 (0.97) 5.5 0.4 - 8.0

8 -3.8 (0.75) -3.6 -7.3 - 0.2

RM2008/00422/00

9 8.5 (0.60) 8 6.5 - 12.0

CONFIDENTIAL

687

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Estonia

Page 2 of 2 Table 7.96 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=9) (N=8) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 9 9 8 8 Mean (Std Err) 7.9 (0.86) -1.0 (0.89) 5.7 (0.87) -2.9 (0.56) Median 7.6 -1.3 5.6 -3.3 Min - Max 3.9 - 12.0 -5.6 - 4.8 2.3 - 9.4 -5.5 - -0.3

CONFIDENTIAL

688

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Slovakia

Page 1 of 2 Table 7.97 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=5) (N=6) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 5 6 Mean (Std Err) 7.7 (0.35) 8.2 (0.47) Median 7.4 8.1 Min - Max 7.0 - 9.0 6.6 - 9.9 5 -0.4 (0.49) -0.3 -2.0 - 0.9

6 6.0 (0.75) 6 3.8 - 9.0

6 -2.2 (0.83) -1.7 -5.4 - 0.0

Week 2 n Mean (Std Err) Median Min - Max

4 6.3 (0.69) 5.9 5.1 - 8.1

4 -1.5 (0.25) -1.5 -1.9 - -0.9

6 5.5 (0.95) 5.5 2.1 - 9.0

6 -2.7 (1.04) -2.6 -5.8 - 0.0

Week 3 n Mean (Std Err) Median Min - Max

4 5.7 (0.92) 6 3.2 - 7.6

4 -2.0 (0.59) -1.5 -3.8 - -1.4

6 5.2 (1.04) 4.6 2.5 - 8.9

6 -3.0 (1.29) -3.5 -6.7 - 2.2

Week 4 n Mean (Std Err) Median Min - Max

4 5.9 (1.17) 6.5 2.6 - 8.0

4 -1.8 (0.87) -1 -4.4 - -0.8

6 4.5 (1.19) 4.4 0.0 - 8.7

6 -3.7 (1.56) -3.7 -9.9 - 2.0

RM2008/00422/00

5 7.2 (0.55) 7.4 5.2 - 8.3

CONFIDENTIAL

689

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Slovakia

Page 2 of 2 Table 7.97 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=5) (N=6) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 5 5 6 6 Mean (Std Err) 6.6 (0.70) -1.0 (0.55) 5.4 (0.86) -2.9 (1.08) Median 6.7 -1 5.2 -2.8 Min - Max 4.6 - 8.3 -2.4 - 0.9 2.9 - 8.0 -6.6 - 0.8

CONFIDENTIAL

690

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Germany

Page 1 of 2 Table 7.98 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=30) (N=31) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 30 31 Mean (Std Err) 8.7 (0.24) 8.6 (0.36) Median 8.6 8.6 Min - Max 6.8 - 11.0 3.5 - 12.0 30 -1.8 (0.40) -1.7 -5.9 - 1.0

31 6.8 (0.41) 6.5 2.6 - 11.6

31 -1.7 (0.30) -1.9 -6.1 - 0.9

Week 2 n Mean (Std Err) Median Min - Max

30 6.3 (0.50) 6.9 0.9 - 12.0

30 -2.4 (0.45) -2 -6.8 - 1.8

31 6.0 (0.50) 5.9 0.9 - 10.4

31 -2.6 (0.40) -2.2 -10.4 - 0.3

Week 3 n Mean (Std Err) Median Min - Max

29 6.1 (0.50) 5.8 1.1 - 11.6

29 -2.5 (0.47) -3 -6.9 - 1.1

30 5.6 (0.55) 5.5 0.6 - 10.9

30 -3.0 (0.46) -2.6 -10.3 - 0.5

Week 4 n Mean (Std Err) Median Min - Max

29 5.7 (0.52) 5.9 0.7 - 10.6

29 -2.9 (0.50) -2.2 -9.4 - 0.9

28 5.2 (0.58) 5.8 0.1 - 10.3

28 -3.7 (0.52) -3.8 -10.9 - 0.5

RM2008/00422/00

30 6.9 (0.45) 7.9 2.1 - 11.5

CONFIDENTIAL

691

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Germany

Page 2 of 2 Table 7.98 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=30) (N=31) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 30 30 31 31 Mean (Std Err) 6.3 (0.47) -2.4 (0.43) 5.9 (0.47) -2.7 (0.38) Median 6.5 -1.9 6 -2.5 Min - Max 1.3 - 11.4 -6.9 - 1.1 1.8 - 10.7 -9.4 - 0.5

CONFIDENTIAL

692

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Hungary

Page 1 of 2 Table 7.99 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=2) (N=4) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 2 4 Mean (Std Err) 7.5 (1.50) 9.4 (0.90) Median 7.5 9.2 Min - Max 6.0 - 9.0 7.6 - 11.8 2 -3.1 (2.00) -3.1 -5.1 - -1.1

4 7.2 (1.04) 7.1 5.1 - 9.3

4 -2.3 (0.45) -2.2 -3.4 - -1.2

Week 2 n Mean (Std Err) Median Min - Max

2 4.9 (1.14) 4.9 3.8 - 6.1

2 -2.6 (0.36) -2.6 -2.9 - -2.2

4 4.8 (0.93) 5 2.5 - 6.5

4 -4.7 (0.49) -4.8 -5.7 - -3.4

Week 3 n Mean (Std Err) Median Min - Max

2 3.4 (1.00) 3.4 2.4 - 4.4

2 -4.1 (0.50) -4.1 -4.6 - -3.6

4 4.8 (1.46) 5.4 0.9 - 7.2

4 -4.7 (0.83) -4.7 -6.7 - -2.7

Week 4 n Mean (Std Err) Median Min - Max

2 3.0 (1.54) 3 1.5 - 4.6

2 -4.5 (0.04) -4.5 -4.5 - -4.4

4 3.9 (2.16) 3.3 0.1 - 8.9

4 -5.6 (1.62) -6.4 -8.4 - -1.0

RM2008/00422/00

2 4.4 (0.50) 4.4 3.9 - 4.9

CONFIDENTIAL

693

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Hungary

Page 2 of 2 Table 7.99 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=2) (N=4) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 2 2 4 4 Mean (Std Err) 3.9 (0.79) -3.6 (0.71) 5.2 (1.33) -4.2 (0.73) Median 3.9 -3.6 5.3 -4.8 Min - Max 3.1 - 4.7 -4.3 - -2.9 2.4 - 7.8 -5.3 - -2.1

CONFIDENTIAL

694

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Russian Federation

Page 1 of 2

Table 7.100 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=18) (N=18) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Baseline n 18 18 Mean (Std Err) 9.7 (0.40) 9.3 (0.37) Median 9.6 8.9 Min - Max 7.6 - 12.0 6.6 - 12.0 18 -2.4 (0.58) -1.9 -9.6 - 0.6

18 6.8 (0.40) 7.3 3.6 - 9.3

18 -2.4 (0.44) -1.9 -6.5 - 0.9

Week 2 n Mean (Std Err) Median Min - Max

18 5.6 (0.59) 5.6 0.9 - 10.4

18 -4.0 (0.76) -3.3 -11.1 - 1.1

18 4.3 (0.63) 3.8 1.0 - 10.3

18 -4.9 (0.60) -5.2 -9.1 - 0.2

Week 3 n Mean (Std Err) Median Min - Max

18 4.8 (0.60) 4.7 0.0 - 10.0

18 -4.8 (0.72) -4.7 -9.8 - 0.0

17 3.4 (0.69) 2.4 0.1 - 10.2

17 -5.7 (0.76) -6.2 -10.6 - 0.9

Week 4 n Mean (Std Err) Median Min - Max

18 4.3 (0.60) 3.7 0.0 - 10.1

18 -5.4 (0.74) -5.4 -9.9 - 0.1

18 2.9 (0.70) 1.8 0.0 - 10.0

18 -6.4 (0.70) -6.8 -12.0 - -0.1

RM2008/00422/00

18 7.3 (0.44) 7.3 2.4 - 10.6

CONFIDENTIAL

695

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: ITT/Russian Federation

Page 2 of 2

Table 7.100 Summary of Daily Reflective Total Nasal Symptom Scores

__________________________________________________________________________ Placebo FF 110mcg QD (N=18) (N=18) _____________________________ _____________________________ Raw Change Raw Change -------------------------------------------------------------------------Weeks 1-4 n 18 18 18 18 Mean (Std Err) 5.6 (0.51) -4.1 (0.66) 4.5 (0.56) -4.8 (0.57) Median 5.7 -3.9 3.8 -4.8 Min - Max 1.9 - 10.3 -10.1 - 0.3 1.2 - 9.9 -8.1 - -0.3

CONFIDENTIAL

696

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.101 Summary of Percent Change from Baseline in Daily Reflective Total Ocular Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 6.6 (0.11) 6.3 (0.12) Median 6.4 6.1 Min - Max 3.9 - 9.0 1.0 - 9.0 155 -19.9 (2.05) -14.3 -98.5 - 64.5

160 5.1 (0.14) 5.1 0.2 - 9.0

160 -18.6 (1.85) -16.4 -94.3 - 85.7

Week 2 n Mean (Std Err) Median Min - Max

153 4.7 (0.18) 4.6 0.0 - 9.0

153 -29.1 (2.53) -26 -100 - 46.9

158 4.4 (0.18) 4.3 0.0 - 9.0

158 -31.0 (2.65) -30.7 -100 - 90.5

Week 3 n Mean (Std Err) Median Min - Max

151 4.4 (0.20) 4.6 0.0 - 9.0

151 -33.0 (2.80) -28.4 -100 - 46.9

156 3.9 (0.19) 3.8 0.0 - 9.0

156 -37.1 (3.16) -36.3 -100 - 157.1

Week 4 n Mean (Std Err) Median Min - Max

149 4.1 (0.21) 4.4 0.0 - 9.0

149 -37.1 (3.03) -31.3 -100 - 45.3

153 3.6 (0.20) 3.4 0.0 - 9.0

153 -44.6 (2.90) -45.2 -100 - 29.7

RM2008/00422/00

155 5.3 (0.16) 5.4 0.1 - 9.0

CONFIDENTIAL

697

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.101 Summary of Percent Change from Baseline in Daily Reflective Total Ocular Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 4.7 (0.18) -29.1 (2.39) 4.2 (0.16) -32.1 (2.44) Median 4.6 -23.9 4.2 -30.2 Min - Max 0.3 - 9.0 -93.7 - 46.0 0.2 - 9.0 -94.3 - 104.8

CONFIDENTIAL

698

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 7.102 Summary of Percent Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Baseline n 155 160 Mean (Std Err) 6.5 (0.13) 6.3 (0.14) Median 6.5 6.3 Min - Max 2.0 - 9.0 1.0 - 9.0 155 -19.3 (2.27) -14.3 -100 - 81.8

160 5.1 (0.16) 5.1 0.0 - 9.0

160 -18.0 (1.96) -13.3 -100 - 57.1

Week 2 n Mean (Std Err) Median Min - Max

153 4.7 (0.19) 4.9 0.0 - 9.0

153 -25.9 (2.69) -21.1 -100 - 94.8

158 4.5 (0.19) 4.6 0.0 - 9.0

158 -27.3 (3.01) -24.3 -100 - 202.0

Week 3 n Mean (Std Err) Median Min - Max

151 4.4 (0.20) 4.6 0.0 - 9.0

151 -30.7 (2.96) -23.2 -100 - 95.5

156 4.1 (0.20) 4 0.0 - 9.0

156 -34.5 (3.05) -33.5 -100 - 128.6

Week 4 n Mean (Std Err) Median Min - Max

149 4.2 (0.22) 4.4 0.0 - 9.0

149 -34.7 (3.23) -28.6 -100 - 113.6

153 3.9 (0.21) 3.7 0.0 - 9.0

153 -40.6 (3.00) -37.4 -100 - 30.6

RM2008/00422/00

155 5.2 (0.17) 5.1 0.0 - 9.0

CONFIDENTIAL

699

Week 1 n Mean (Std Err) Median Min - Max

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 7.102 Summary of Percent Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Scores __________________________________________________________________________ Placebo FF 110mcg QD (N=155) (N=160) _____________________________ _____________________________ Raw Pct Change Raw Pct Change -------------------------------------------------------------------------Weeks 1-4 n 155 155 160 160 Mean (Std Err) 4.7 (0.18) -27.1 (2.54) 4.4 (0.17) -29.7 (2.55) Median 5 -20.4 4.3 -27.3 Min - Max 0.0 - 9.0 -99.6 - 96.4 0.0 - 9.0 -100 - 117.1

CONFIDENTIAL

700

RM2008/00422/00

CONFIDENTIAL

RM2008/00422/00

Safety Data Source Tables Page

Table 8.1 Summary of Extent of Exposure to Study Medication (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

704

Table 8.2 Listing of Exposure to Study Medication (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

705

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text (Intent-to-Treat Population) . . . . . . . . . . . . . . .

717

Table 8.4 Summary of All Adverse Events During the Screening Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

725

Table 8.5 Summary of All Adverse Events During the Treatment Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

727

Table 8.6 Summary of Adverse Events with Incidence Rate >3% and More Common than Placebo During the Treatment Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

731

Table 8.7 Summary of Adverse Events with Incidence Rate 1% to 3% and More Common than Placebo During the Treatment Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

732

Table 8.8 Summary of All Adverse Events During the Post-Treatment Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

733

Table 8.9 Listing of Subject Numbers for Individual Adverse Events (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

734

Table 8.10 Listing of All Adverse Events During the Study Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

743

Table 8.11 Listing of All Adverse Events During the Study Period Sorted by Preferred Term (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .

808

Table 8.12 Summary of Drug-Related Adverse Events During the Study Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

879

Table 8.13 Listing of Drug-Related Adverse Events During the Study Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

880

Table 8.14 Listing of Serious Adverse Events During the Screening Period (Screen Failure Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

896

701

CONFIDENTIAL

RM2008/00422/00

Table 8.15 Listing of Serious Adverse Events During the Study Period (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

897

Table 8.16 Summary of Adverse Events Causing Withdrawal from the Study (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

898

Table 8.17 Listing of Adverse Events Causing Withdrawal from Study (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

899

Table 8.18 Summary of All Adverse Events During the Treatment Period (ITT/Age 12 - <18 years Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

901

Table 8.19 Summary of All Adverse Events During the Treatment Period (ITT/Age 18 - <65 years Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

902

Table 8.20 Summary of All Adverse Events During the Treatment Period (Intent-to-Treat/Age >=65 years Population) . . . . . . . . . . . . . . . . . . . . . .

906

Table 8.21 Summary of All Adverse Events During the Treatment Period (Intent-to-Treat/Female Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

907

Table 8.22 Summary of All Adverse Events During the Treatment Period (Intent-to-Treat/Male Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

910

Table 8.23 Definitions of Normal Ranges for Laboratory Values (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

912

Table 8.24 Summary of Laboratory Values (Intent-to-Treat Population). . . . .

918

Table 8.25 Summary of Laboratory Data Outside the Normal Range (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

928

Table 8.26 Summary of Laboratory Shifts from Baseline to Endpoint (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

943

Table 8.27 Listing of Laboratory Data for Subjects with at Least One Abnormal Value Post-Randomization in Hematology (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

949

Table 8.28 Listing of Laboratory Data for Subjects with at Least One Abnormal Value Post-Randomization in Chemistry (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1201

Table 8.29 Summary of Nasal Examinations (Intent-to-Treat Population) . . .

1308

Table 8.30 Summary of Nasal Examination Shifts from Baseline to Endpoint (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1311

Table 8.31 Listing of Subjects with at least one Occurrence of Worsening Ulcers at any time Post-Baseline (Intent-to-Treat Population) . . . . . . . . .

1312

702

CONFIDENTIAL

RM2008/00422/00

Table 8.32 Listing of Subjects with at least one Occurrence of Worsening Mucosal Bleeding at any time Post-Baseline (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1327

Table 8.33 Listing of Subjects with at Least One Abnomal Nasal Examination Result Post-Baseline (Intent-to-Treat Population) . . . . . . . .

1371

Table 8.34 Listing of Subjects With Clinical Evidence of Nasal Candidiasis (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1427

Table 8.35 Summary of Vitals Signs (Intent-to-Treat Population) . . . . . . . . . .

1428

Table 8.36 Summary of Change from Baseline in Vital Signs at Endpoint (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1430

703

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1 Table 8.1 Summary of Extent of Exposure to Study Medication

Placebo FF 110mcg QD Total (N=155) (N=160) (N=315) -----------------------------------------------------------------------------------------------------Number of subjects, n(%) n 155 160 315 1-7 days 1 (<1%) 2 (1%) 3 (<1%) 8-14 days 1 (<1%) 0 1 (<1%) 15-21 days 3 (2%) 1 (<1%) 4 (1%) 22-27 days 17 (11%) 16 (10%) 33 (10%) 28-31 days 122 (79%) 133 (83%) 255 (81%) >31 days 11 (7%) 8 (5%) 19 (6%) Exposure (days)

155 28.6 3.35 29.0 6 36

160 28.5 3.37 29.0 4 36

315 28.6 3.36 29.0 4 36

CONFIDENTIAL

704

n Mean SD Median Min. Max.

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Treatment

Page 1 of 12 Table 8.2 Listing of Exposure to Study Medication Inv.

Subj.

Start Date of Study Med.

Stop Date of Study Med.

Duration (days)

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

705

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Eye disorders Conjunctival haemorrhage Subconjunctival Hemorrhage Eye pruritus itchy eye Ocular hyperaemia red eye Gastrointestinal disorders

Abdominal pain upper

Nausea

717

Stomatitis Toothache Chest pain

chest pain

Facial pain Pain

pain left face Body Aches

Hepatobiliary disorders

Gallbladder pain Hyperbilirubinaemia

cholecystic pain Hyperbilirubinaemia

Infections and infestations

Bronchitis

Bronchitis acute bronchitis cystitis ear infection Stomach virus stomach flu Herpes zoster

Cystitis Ear infection Gastroenteritis viral Herpes zoster

RM2008/00422/00

General disorders and administration site conditions

CONFIDENTIAL

Constipation Diarrhoea Dyspepsia

stomach ache stomach pain upper gastric pain Consitpation diarrhoe Heart Burn dyspepsia Nausea nausea stomatitis tooth pain toothache

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

CONFIDENTIAL

718

RM2008/00422/00

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Infections and infestations Hordeolum stye on right lower eye lid Influenza Flu flu Localised infection Naval infection Lower respiratory tract Chest Infection infection Nasopharyngitis Chest cold with cough Cold symptoms Common Cold Common cold cold symptoms common cold sore throat/ cold symptoms Oral herpes herpes simplex labialis Otitis media Left serous otitis Respiratory tract infection Acute respiratory virus viral infection Sialoadenitis infected salivery gland (left) Sinusitis sinusitis Tinea cruris worsening ofTinea Crura (groin) Tonsillitis tonsillitis Upper respiratory tract URI infection Upper Respiratory Tract Infection upper respiratory infection Urinary tract infection Urinary Tract Infection Viral infection Viral Illness Viral Syndrome

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Infections and infestations Viral infection Viral syndrome acute viral syndrome Injury, poisoning and procedural complications

Injury Skeletal injury

Investigations

Alanine aminotransferase increased

Increase ALAT twice Raised ALAT 189 U / L Raised ASAT , 343 U /L Raised CPK ( 511 U/L ) Non Specific T Wave Changes - Decreased V1 to V3

Diabetes mellitus Hyperglycaemia

Diabetes Hyperglucosaemia

Musculoskeletal and connective tissue disorders

Arthralgia

Hip Pain Intermittent Ankle Pain Intermittent Knee Pain Joint pain Knee Pain L hip Pain Back Pain Sore Back back pain backpain Vertebral pain pain right shoulder

Back pain

Bone pain Musculoskeletal pain

RM2008/00422/00

Metabolism and nutrition disorders

CONFIDENTIAL

719

Aspartate aminotransferase increased Blood creatine phosphokinase increased Electrocardiogram T wave abnormal

Accident. Stab wound of left foot. contusion of rib left side

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Myalgia Generalized muscles ache due to workout Nervous system disorders

Dizziness Headache

Migraine

720

Reproductive system and breast disorders

Respiratory, thoracic and mediastinal disorders

Dysmenorrhoea

Cough Dysphonia Epistaxis

Abdominal menses Menstrual Menstrual menstrual

pain due to cramps pain pain

RM2008/00422/00

Dry Cough cough occasional cough croaky voice Bilateral Nasal Bleeding Bilateral mucosal bleeding Bleeding right nostril Left Nasal bleeding small nasal septal punctate area in left nostril Left Nostrial muscosal bleeding

CONFIDENTIAL

Sinus headache Tension headache

Dizziness dizziness Headache Headaches head ache headache Migraine Migraine Headache Sinus Headache Stress Headache

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

CONFIDENTIAL

721

RM2008/00422/00

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Respiratory, thoracic and mediastinal disorders Epistaxis Left nasal mucosa with blood Left nostril bleed Left nostril bleeding Mild Left nostril septum mucosal bleeding Mild mucosal bleeding in left nostril Mucosal bleeding in R nostril Mucosal bleeding in left nostril Nose Bleed Nose bleed R nostril epistaxis Right Nostril Post Bleed Right nasal mucosal bleeding Two mild small septal bleeding areas in left nostril bilateral bleeding- nose blood streaks in nasal mucosa epistaxis right nostril epistaxsis epitaxis left nostril bleeding nasal bleeding nose bleed one small nasal septal bleeding area in right nostril right nostril beeding

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

CONFIDENTIAL

722

RM2008/00422/00

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Respiratory, thoracic and mediastinal disorders Epistaxis right nostril bleed right nostril bleeding small amount of blood on septal mucosa noted on nasal exam of right nostril Hiccups hicups Increased upper airway Throat secretion secretion Nasal discomfort Bilateral nasal septal irritation Occasional left nostril burning when inhaling study drug Nasal dryness Nose dryness dryness in the nose dryness of nose Nasal polyps Left nostril turbinate large polyp Right nostril septum large polyp enlargement of polypos in right nostril turbinates Nasal septum ulceration small ulceration of left nasal septum Nasal ulcer Pt has Med HX of <2mm ulcer. Ulcer worsened to >4mm few nasal ulcerations left inferior turbinate small ulceration left inferior turbinate Pharyngolaryngeal pain Sore Throat sore throat

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain throat pain Sneezing Increase in frequency of episodes of multiple sneezes. Increased frequency in episodes of multiple sneezes. sneezing Skin and subcutaneous tissue disorders

723

Pruritus Scab

Skin lesion Surgical and medical procedures

Dental operation

dental surgery

RM2008/00422/00

Skin inflammation

Blister in Nose eczema Left Lafteral petechiae nasal mucosal pruritus Bilateral Nasal crusting on septum Crust lesion on right nasal septum Healing scab left septal wall of nose Scab with blood r nostril crust lesion on left septum crusts in nose nasal exam of right nostril showed bloody scab with crust skin inflammation upper lip and nose skin lesion around nostrils

CONFIDENTIAL

Blister Eczema Petechiae

Protocol: FFU111439 Population: Intent-to-Treat

Page 8 of 8

Table 8.3 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ----------------------------------------------------------------------------------------------------------Vascular disorders Hypertension High blood pressure

CONFIDENTIAL

724

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 8.4 Summary of All Adverse Events During the Screening Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) -------------------------------------------------------------------------------ANY EVENT 10 (6%) 8 (5%) 1 (<1%) 0 0 0 1 (<1%) 0

4 1 1 1 0 1

Nervous system disorders Any event Headache Dizziness

4 (3%) 3 (2%) 1 (<1%)

0 0 0

Gastrointestinal disorders Any event Abdominal pain upper Constipation Dyspepsia

2 (1%) 1 (<1%) 1 (<1%) 0

1 (<1%) 0 0 1 (<1%)

Investigations Any event Alanine aminotransferase increased Electrocardiogram T wave abnormal

1 (<1%) 0 1 (<1%)

1 (<1%) 1 (<1%) 0

Musculoskeletal and connective tissue disorders Any event Arthralgia Musculoskeletal pain

1 (<1%) 0 1 (<1%)

1 (<1%) 1 (<1%) 0

Metabolism and nutrition disorders Any event

0

1 (<1%)

(3%) (<1%) (<1%) (<1%) (<1%)

CONFIDENTIAL

725

Infections and infestations Any event Cystitis Gastroenteritis viral Localised infection Oral herpes Viral infection

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 8.4 Summary of All Adverse Events During the Screening Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) -------------------------------------------------------------------------------Diabetes mellitus 0 1 (<1%) Reproductive system and breast disorders Any event Dysmenorrhoea

1 (<1%) 1 (<1%)

0 0

CONFIDENTIAL

726

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 4

Table 8.5 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) --------------------------------------------------------------------------------ANY EVENT 52 (34%) 67 (42%) (14%) (8%) (1%) (<1%) (1%) (<1%) (<1%) (<1%) (1%)

Infections and infestations Any event Nasopharyngitis Upper respiratory tract infection Bronchitis Respiratory tract infection viral Viral infection Influenza Ear infection Gastroenteritis viral Herpes zoster Hordeolum Lower respiratory tract infection Otitis media Sialoadenitis Sinusitis

13 2 1 1 0 1 1 0 1 1 0 1 0 1 1

(8%) (1%) (<1%) (<1%)

(<1%) (<1%)

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

31 24 3 3 1 2 1 1 0 1 0 1 0

(19%) (15%) (2%) (2%) (<1%) (1%) (<1%) (<1%)

21 8 3 2 3 2 1 1 0 0 1 0 1 0 0

(13%) (5%) (2%) (1%) (2%) (1%) (<1%) (<1%)

(<1%) (<1%)

(<1%) (<1%)

RM2008/00422/00

21 13 2 1 2 1 1 1 2 0 1 0 1

CONFIDENTIAL

727

Respiratory, thoracic and mediastinal disorders Any event Epistaxis Cough Pharyngolaryngeal pain Nasal dryness Nasal ulcer Nasal discomfort Nasal polyps Sneezing Dysphonia Hiccups Increased upper airway secretion Nasal septum ulceration

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 4

Table 8.5 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) --------------------------------------------------------------------------------Tinea cruris 0 1 (<1%) Tonsillitis 1 (<1%) 0 Urinary tract infection 1 (<1%) 0

728

11 (7%) 8 (5%) 2 (1%) 0 1 (<1%) 0

Skin and subcutaneous tissue disorders Any event Scab Blister Eczema Petechiae Pruritus Skin inflammation Skin lesion

6 (4%) 3 (2%) 1 (<1%) 1 (<1%) 0 1 (<1%) 0 0

7 (4%) 4 (3%) 0 0 1 (<1%) 0 1 (<1%) 1 (<1%)

Musculoskeletal and connective tissue disorders Any event Arthralgia Back pain Bone pain Myalgia

3 (2%) 1 (<1%) 2 (1%) 1 (<1%) 0

6 (4%) 4 (3%) 2 (1%) 0 1 (<1%)

Gastrointestinal disorders Any event Nausea Abdominal pain upper

2 (1%) 1 (<1%) 1 (<1%)

6 (4%) 2 (1%) 1 (<1%)

RM2008/00422/00

12 (8%) 9 (6%) 2 (1%) 1 (<1%) 0 1 (<1%)

CONFIDENTIAL

Nervous system disorders Any event Headache Migraine Dizziness Sinus headache Tension headache

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 4

Table 8.5 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) --------------------------------------------------------------------------------Toothache 0 2 (1%) Diarrhoea 0 1 (<1%) Dyspepsia 0 1 (<1%) Stomatitis 0 1 (<1%) 1 (<1%) 0 1 (<1%) 0

Reproductive system and breast disorders Any event Dysmenorrhoea

2 2

(1%) (1%)

1 (<1%) 1 (<1%)

Eye disorders Any event Conjunctival haemorrhage Eye pruritus Ocular hyperaemia

1 (<1%) 0 1 (<1%) 1 (<1%)

1 (<1%) 1 (<1%) 0 0

Injury, poisoning and procedural complications Any event Injury Skeletal injury

0 0 0

2 (1%) 1 (<1%) 1 (<1%)

Hepatobiliary disorders Any event Gallbladder pain

0 0

1 (<1%) 1 (<1%)

Investigations Any event Alanine aminotransferase increased

1 (<1%) 1 (<1%)

0 0

RM2008/00422/00

2 (1%) 1 (<1%) 0 1 (<1%)

CONFIDENTIAL

729

General disorders and administration site conditions Any event Chest pain Facial pain Pain

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 4

Table 8.5 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) --------------------------------------------------------------------------------Aspartate aminotransferase increased 1 (<1%) 0 Blood creatine phosphokinase increased 1 (<1%) 0 0 0

1 (<1%) 1 (<1%)

Vascular disorders Any event Hypertension

1 (<1%) 1 (<1%)

0 0

730

CONFIDENTIAL

Surgical and medical procedures Any event Dental operation

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.6 Summary of Adverse Events with Incidence Rate >3% and More Common than Placebo During the Treatment Period Placebo FF 110mcg QD Preferred Term (N=155) (N=160) -------------------------------------------------------Any event 52 (34%) 67 (42%) Epistaxis Nasopharyngitis

13 2

(8%) (1%)

24 (15%) 8 (5%)

CONFIDENTIAL

731

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.7 Summary of Adverse Events with Incidence Rate 1% to 3% and More Common than Placebo During the Treatment Period

732

CONFIDENTIAL

Placebo FF 110mcg QD Preferred Term (N=155) (N=160) -----------------------------------------------------------------------------Scab 3 (2%) 4 (3%) Arthralgia 1 (<1%) 4 (3%) Cough 2 (1%) 3 (2%) Pharyngolaryngeal pain 1 (<1%) 3 (2%) Upper respiratory tract infection 1 (<1%) 3 (2%) Bronchitis 1 (<1%) 2 (1%) Nasal ulcer 1 (<1%) 2 (1%) Nausea 1 (<1%) 2 (1%) Respiratory tract infection viral 0 3 (2%) Viral infection 1 (<1%) 2 (1%) Toothache 0 2 (1%)

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.8 Summary of All Adverse Events During the Post-Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) ------------------------------------------------------------------------------ANY EVENT 1 (<1%) 2 (1%) 1 (<1%) 1 (<1%)

0 0

Metabolism and nutrition disorders Any event Hyperglycaemia

0 0

1 (<1%) 1 (<1%)

Respiratory, thoracic and mediastinal disorders Any event Epistaxis

0 0

1 (<1%) 1 (<1%)

733

CONFIDENTIAL

Hepatobiliary disorders Any event Hyperbilirubinaemia

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 9

Table 8.9 Listing of Subject Numbers for Individual Adverse Events

No. System Organ Class with Preferred Term Treatment Event Subject Numbers ----------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

734

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 65 Table 8.10 Listing of All Adverse Events During the Study Period

Treatment: Placebo

Treatment Outcome/ Start Age(y)/ Onset Date/ Treatment Date/ Maximum Action Sex/ Date of phase/Time Treatment Intensity/ Taken/ Inv./ Race/ Preferred Term/ Resolution/ since 1st Stop Serious/ Relation to Subj Ethnicity VERBATIM TEXT Duration dose(days) Date Withdrawal Study Drug ---------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

743

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 71 Table 8.11 Listing of All Adverse Events During the Study Period Sorted by Preferred Term

Treatment Outcome/ Start Age(y)/ Onset Date/ Treatment Date/ Maximum Action Treatment/ Sex/ Date of phase/Time Treatment Intensity/ Taken/ Invid./ Race/ Onset Preferred Term/ Resolution/ since 1st Stop Serious/ Relation to Subj. Ethnicity Date VERBATIM TEXT Duration dose(days) Date Withdrawal Study Drug -----------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

808

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.12 Summary of Drug-Related Adverse Events During the Study Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) -------------------------------------------------------------------------------ANY EVENT 11 (7%) 24 (15%) 10 (6%) 6 (4%) 2 (1%) 1 (<1%) 1 (<1%) 2 (1%) 0 1 (<1%) 0

21 19 1 1 1 0 1 0 1

(13%) (12%) (<1%) (<1%) (<1%) (<1%) (<1%)

879

Nervous system disorders Any event Headache Sinus headache

2 2 0

(1%) (1%)

1 (<1%) 0 1 (<1%)

Skin and subcutaneous tissue disorders Any event Scab

1 (<1%) 1 (<1%)

1 (<1%) 1 (<1%)

General disorders and administration site conditions Any event Facial pain

0 0

1 (<1%) 1 (<1%)

CONFIDENTIAL

Respiratory, thoracic and mediastinal disorders Any event Epistaxis Nasal dryness Nasal discomfort Nasal ulcer Sneezing Increased upper airway secretion Nasal septum ulceration Pharyngolaryngeal pain

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 16

Table 8.13 Listing of Drug-Related Adverse Events During the Study Period

Treatment: Placebo

Treatment Outcome/ Start Age(y)/ Onset Date/ Treatment Date/ Maximum Sex/ Date of phase/Time Treatment Intensity/ Inv./ Race/ Preferred Term/ Resolution/ since 1st Stop Serious/ Action Subj Ethnicity VERBATIM TEXT Duration dose(days) Date Withdrawal taken ---------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

880

RM2008/00422/00

Protocol: FFU111439 Population: Screen Failure

Page 1 of 1

Table 8.14 Listing of Serious Adverse Events During the Screening Period

No data to report

CONFIDENTIAL

896

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.15 Listing of Serious Adverse Events During the Study Period

No data to report

CONFIDENTIAL

897

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.16 Summary of Adverse Events Causing Withdrawal from the Study

System Organ Class Placebo FF 110mcg QD Preferred Term (N=155) (N=160) ------------------------------------------------------------------------------ANY EVENT 1 (<1%) 1 (<1%) Infections and infestations Any event Lower respiratory tract infection

1 (<1%) 1 (<1%)

0 0

Metabolism and nutrition disorders Any event Diabetes mellitus

0 0

1 (<1%) 1 (<1%)

CONFIDENTIAL

898

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 8.17 Listing of Adverse Events Causing Withdrawal from Study

Treatment: Placebo

Treatment Outcome/ Start Age(y)/ Onset Date/ Treatment Date/ Action Sex/ Date of phase/Time Treatment Maximum Taken/ Inv./ Race/ Preferred Term/ Resolution/ since 1st Stop Intensity/ Relation to Subj Ethnicity VERBATIM TEXT Duration dose(days) Date Serious/ Study Drug ----------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

899

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Age 12 - <18 years

Page 1 of 1

Table 8.18 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=9) (N=9) -------------------------------------------------------------------------ANY EVENT 0 2 (22%) Infections and infestations Any event Bronchitis

0 0

1 (11%) 1 (11%)

Respiratory, thoracic and mediastinal disorders Any event Epistaxis

0 0

1 (11%) 1 (11%)

CONFIDENTIAL

901

RM2008/00422/00

Protocol: FFU111439 Population: ITT/Age 18

-

Page 1 of 4

<65 years

Table 8.19 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=141) (N=146) --------------------------------------------------------------------------------ANY EVENT 50 (35%) 64 (44%) (15%) (9%) (1%) (<1%) (1%) (<1%) (<1%) (<1%) (1%)

Infections and infestations Any event Nasopharyngitis Upper respiratory tract infection Respiratory tract infection viral Viral infection Bronchitis Influenza Ear infection Gastroenteritis viral Herpes zoster Hordeolum Lower respiratory tract infection Otitis media Sialoadenitis Sinusitis

13 2 1 0 1 1 1 0 1 1 0 1 0 1 1

(9%) (1%) (<1%)

(<1%) (<1%)

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

30 23 3 3 1 2 1 1 0 1 0 1 0

(21%) (16%) (2%) (2%) (<1%) (1%) (<1%) (<1%)

20 8 3 3 2 1 1 1 0 0 1 0 1 0 0

(14%) (5%) (2%) (2%) (1%) (<1%) (<1%) (<1%)

(<1%) (<1%)

(<1%) (<1%)

RM2008/00422/00

21 13 2 1 2 1 1 1 2 0 1 0 1

CONFIDENTIAL

902

Respiratory, thoracic and mediastinal disorders Any event Epistaxis Cough Pharyngolaryngeal pain Nasal dryness Nasal ulcer Nasal discomfort Nasal polyps Sneezing Dysphonia Hiccups Increased upper airway secretion Nasal septum ulceration

Protocol: FFU111439 Population: ITT/Age 18

-

Page 2 of 4

<65 years

Table 8.19 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=141) (N=146) --------------------------------------------------------------------------------Tinea cruris 0 1 (<1%) Tonsillitis 1 (<1%) 0 Urinary tract infection 1 (<1%) 0

903

10 (7%) 7 (5%) 2 (1%) 0 1 (<1%) 0

Skin and subcutaneous tissue disorders Any event Scab Blister Eczema Petechiae Skin inflammation Skin lesion

5 (4%) 3 (2%) 1 (<1%) 1 (<1%) 0 0 0

7 (5%) 4 (3%) 0 0 1 (<1%) 1 (<1%) 1 (<1%)

Musculoskeletal and connective tissue disorders Any event Arthralgia Back pain Bone pain Myalgia

3 (2%) 1 (<1%) 2 (1%) 1 (<1%) 0

6 (4%) 4 (3%) 2 (1%) 0 1 (<1%)

Gastrointestinal disorders Any event Nausea Abdominal pain upper Toothache

2 (1%) 1 (<1%) 1 (<1%) 0

6 (4%) 2 (1%) 1 (<1%) 2 (1%)

RM2008/00422/00

12 (9%) 9 (6%) 2 (1%) 1 (<1%) 0 1 (<1%)

CONFIDENTIAL

Nervous system disorders Any event Headache Migraine Dizziness Sinus headache Tension headache

Protocol: FFU111439 Population: ITT/Age 18

-

Page 3 of 4

<65 years

Table 8.19 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=141) (N=146) --------------------------------------------------------------------------------Diarrhoea 0 1 (<1%) Dyspepsia 0 1 (<1%) Stomatitis 0 1 (<1%) 1 (<1%) 0 1 (<1%) 0

Reproductive system and breast disorders Any event Dysmenorrhoea

2 2

1 (<1%) 1 (<1%)

Injury, poisoning and procedural complications Any event Injury Skeletal injury

0 0 0

2 (1%) 1 (<1%) 1 (<1%)

Eye disorders Any event Conjunctival haemorrhage

0 0

1 (<1%) 1 (<1%)

Hepatobiliary disorders Any event Gallbladder pain

0 0

1 (<1%) 1 (<1%)

Investigations Any event Alanine aminotransferase increased Aspartate aminotransferase increased Blood creatine phosphokinase increased

1 1 1 1

(1%) (1%)

(<1%) (<1%) (<1%) (<1%)

0 0 0 0

RM2008/00422/00

2 (1%) 1 (<1%) 0 1 (<1%)

CONFIDENTIAL

904

General disorders and administration site conditions Any event Chest pain Facial pain Pain

Protocol: FFU111439 Population: ITT/Age 18

-

Page 4 of 4

<65 years

Table 8.19 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=141) (N=146) --------------------------------------------------------------------------------Surgical and medical procedures Any event 0 1 (<1%) Dental operation 0 1 (<1%) Vascular disorders Any event Hypertension

1 (<1%) 1 (<1%)

0 0

CONFIDENTIAL

905

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat/Age >=65 years

Page 1 of 1

Table 8.20 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=5) (N=5) ------------------------------------------------------------------------------ANY EVENT 2 (40%) 1 (20%) 1 (20%) 1 (20%) 1 (20%)

0 0 0

Nervous system disorders Any event Headache

0 0

1 (20%) 1 (20%)

Skin and subcutaneous tissue disorders Any event Pruritus

1 (20%) 1 (20%)

0 0

CONFIDENTIAL

906

Eye disorders Any event Eye pruritus Ocular hyperaemia

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat/Female

Page 1 of 3

Table 8.21 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=110) (N=103) -------------------------------------------------------------------------------ANY EVENT 44 (40%) 48 (47%)

Nervous system disorders Any event Headache

(15%) (9%) (<1%) (<1%) (<1%) (<1%) (2%) (<1%)

9 0 1 0 1 1 1 1 1 1 1 1

(8%)

(<1%) (<1%) (<1%)

(<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%) (<1%)

11 (10%) 8 (7%)

23 18 2 2 1 1 0 1 1 0 0 0

(22%) (17%) (2%) (2%) (<1%) (<1%) (<1%) (<1%)

13 (13%) 5 (5%) 2 (2%) 3 (3%) 2 (2%) 2 (2%) 0 0 0 0 0 0 8 5

(8%) (5%)

RM2008/00422/00

Infections and infestations Any event Nasopharyngitis Bronchitis Respiratory tract infection viral Upper respiratory tract infection Viral infection Gastroenteritis viral Herpes zoster Influenza Sialoadenitis Sinusitis Urinary tract infection

16 10 1 1 1 1 2 1 0 1 1 1

CONFIDENTIAL

907

Respiratory, thoracic and mediastinal disorders Any event Epistaxis Nasal ulcer Pharyngolaryngeal pain Cough Nasal discomfort Nasal dryness Nasal polyps Dysphonia Hiccups Nasal septum ulceration Sneezing

Protocol: FFU111439 Population: Intent-to-Treat/Female

Page 2 of 3

Table 8.21 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=110) (N=103) -------------------------------------------------------------------------------Migraine 2 (2%) 2 (2%) Dizziness 1 (<1%) 0 Sinus headache 0 1 (<1%) Tension headache 1 (<1%) 0 6 (5%) 3 (3%) 1 (<1%) 1 (<1%) 0 1 (<1%) 0 0

4 1 0 0 1 0 1 1

Musculoskeletal and connective tissue disorders Any event Arthralgia Back pain Bone pain Myalgia

3 (3%) 1 (<1%) 2 (2%) 1 (<1%) 0

6 (6%) 4 (4%) 2 (2%) 0 1 (<1%)

Gastrointestinal disorders Any event Nausea Toothache Abdominal pain upper Diarrhoea Dyspepsia

1 (<1%) 1 (<1%) 0 0 0 0

4 1 2 1 1 1

General disorders and administration site conditions Any event Chest pain

2 (2%) 1 (<1%)

1 (<1%) 0

(4%) (<1%) (<1%) (<1%) (<1%)

RM2008/00422/00

(4%) (<1%) (2%) (<1%) (<1%) (<1%)

CONFIDENTIAL

908

Skin and subcutaneous tissue disorders Any event Scab Blister Eczema Petechiae Pruritus Skin inflammation Skin lesion

Protocol: FFU111439 Population: Intent-to-Treat/Female

Page 3 of 3

Table 8.21 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=110) (N=103) -------------------------------------------------------------------------------Facial pain 0 1 (<1%) Pain 1 (<1%) 0 2 2

(2%) (2%)

1 (<1%) 1 (<1%)

Eye disorders Any event Conjunctival haemorrhage Eye pruritus Ocular hyperaemia

1 (<1%) 0 1 (<1%) 1 (<1%)

1 (<1%) 1 (<1%) 0 0

Injury, poisoning and procedural complications Any event Injury Skeletal injury

0 0 0

2 (2%) 1 (<1%) 1 (<1%)

Investigations Any event Alanine aminotransferase increased Aspartate aminotransferase increased Blood creatine phosphokinase increased

1 1 1 1

Surgical and medical procedures Any event Dental operation

0 0

1 (<1%) 1 (<1%)

Vascular disorders Any event Hypertension

1 (<1%) 1 (<1%)

0 0

(<1%) (<1%) (<1%) (<1%)

CONFIDENTIAL

909

Reproductive system and breast disorders Any event Dysmenorrhoea

0 0 0 0

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat/Male

Page 1 of 2

Table 8.22 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=45) (N=57) -------------------------------------------------------------------------------ANY EVENT 8 (18%) 19 (33%) 8 (14%) 6 (11%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) 0

Infections and infestations Any event Nasopharyngitis Ear infection Hordeolum Influenza Lower respiratory tract infection Otitis media Tinea cruris Tonsillitis Upper respiratory tract infection

4 2 0 0 0 1 0 0 1 0

(9%) (4%)

8 (14%) 3 (5%) 1 (2%) 1 (2%) 1 (2%) 0 1 (2%) 1 (2%) 0 1 (2%)

Nervous system disorders Any event Headache

1 1

(2%) (2%)

3 3

(5%) (5%)

Gastrointestinal disorders Any event Abdominal pain upper Nausea Stomatitis

1 1 0 0

(2%) (2%)

2 0 1 1

(4%)

(2%) (2%)

(2%) (2%)

RM2008/00422/00

5 (11%) 3 (7%) 1 (2%) 0 0 0 1 (2%)

CONFIDENTIAL

910

Respiratory, thoracic and mediastinal disorders Any event Epistaxis Cough Increased upper airway secretion Nasal dryness Pharyngolaryngeal pain Sneezing

Protocol: FFU111439 Population: Intent-to-Treat/Male

Page 2 of 2

Table 8.22 Summary of All Adverse Events During the Treatment Period

System Organ Class Placebo FF 110mcg QD Preferred Term (N=45) (N=57) -------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any event 0 3 (5%) Scab 0 3 (5%) Hepatobiliary disorders Any event Gallbladder pain

0 0

1 1

(2%) (2%)

CONFIDENTIAL

911

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 6 Table 8.23 Definitions of Normal Ranges for Laboratory Values

Age Range Normal Range _________ _____________ Lab Parameter Units Sex Low High Low High --------------------------------------------------------------------------Chemistry Alanine Amino Transferase IU/L F 12 12 0 45 13 71 0 48

Albumin

IU/L

0 0

45 48

F

12

71

32

50

M

12

80

32

50

F

12 13 17 20

12 13 19 71

60 60 30 20

415 350 165 125

M

12 13 16 20

12 15 19 80

60 60 30 20

415 500 225 125

Aspartate Amino Transferase

Calcium

Creatine Kinase

IU/L

F

12 65

64 71

0 0

42 55

M

12 69

63 80

0 0

42 55

MMOL/L

F

12

71

2.12

2.56

M

12

80

2.12

2.56

IU/L

F

28

28

0

190

RM2008/00422/00

12 80

912

12 13

CONFIDENTIAL

Alkaline Phosphatase

G/L

M

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 6 Table 8.23 Definitions of Normal Ranges for Laboratory Values

Age Range Normal Range _________ _____________ Lab Parameter Units Sex Low High Low High --------------------------------------------------------------------------Creatinine UMOL/L F 12 12 27 88 13 71 44 124

Direct Bilirubin

MMOL/L

913

12 13

12 80

27 44

88 124

F

12

71

0

6

M

12

80

0

6

F

12 13 50

12 49 71

3.3 3.9 3.9

6.1 6.4 6.9

M

12 13 50

12 49 80

3.3 3.9 3.9

6.1 6.4 6.9

IU/L

F

28

28

0

250

Potassium

MMOL/L

F

12 13

12 71

3.5 3.5

5.5 5.3

M

12 13

12 80

3.5 3.5

5.5 5.3

F

12

71

135

146

M

12

80

135

146

F

12

71

0

22

Sodium

Total Bilirubin

MMOL/L

UMOL/L

RM2008/00422/00

Lactate Dehydrogenase

CONFIDENTIAL

Glucose

UMOL/L

M

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 6 Table 8.23 Definitions of Normal Ranges for Laboratory Values

Age Range Normal Range _________ _____________ Lab Parameter Units Sex Low High Low High --------------------------------------------------------------------------Total Bilirubin UMOL/L M 12 80 0 22 Total Protein

MMOL/L

914 Hematology Basophils

Basophils (percentage)

Eosinophils (percentage)

%

GI/L

%

12 13 65

12 64 71

55 60 58

80 85 81

M

12 13 69

12 63 80

55 60 58

80 85 81

F

12 13 65

12 64 71

3 2.5 2.5

7.5 9 10.5

M

12 13 69

12 63 80

3 2.5 2.5

7.5 9 10.5

F

12

71

0

0.2

M

12

80

0

0.2

F

12

71

0

2

M

12

80

0

2

F

12

71

0.05

0.55

M

12

80

0.05

0.55

F

12

17

0

5

RM2008/00422/00

Eosinophils

GI/L

F

CONFIDENTIAL

Urea

G/L

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 6 Table 8.23 Definitions of Normal Ranges for Laboratory Values

Age Range Normal Range _________ _____________ Lab Parameter Units Sex Low High Low High --------------------------------------------------------------------------Eosinophils (percentage) % F 18 71 0 7

Hematocrit

Lymphocytes

Lymphocytes (percentage)

GI/L

%

GI/L

17 80

0 0

5 7

F

12 18 65

17 64 71

0.36 0.35 0.33

0.49 0.46 0.46

M

12 18

80 63

0.36 0.41

0.49 0.5

F

12 18 65

17 64 71

120 120 111

160 156 155

M

12 18 69

17 63 80

120 138 118

160 172 168

F

12

71

0.85

4.1

M

12

80

0.85

4.1

F

12 18

17 71

21 16

51 46

M

12 18

17 80

21 16

51 46

F

12

71

0.2

1.1

RM2008/00422/00

Monocytes

G/L

12 18

CONFIDENTIAL

915

Hemoglobin

1

M

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 6 Table 8.23 Definitions of Normal Ranges for Laboratory Values

Age Range Normal Range _________ _____________ Lab Parameter Units Sex Low High Low High --------------------------------------------------------------------------Monocytes GI/L M 12 80 0.2 1.1 Monocytes (percentage)

916

Red Blood Cell Count

Segmented Neutrophils

Total Neutrophils

TI/L

GI/L

%

GI/L

12 18

17 71

0 0

10 12

M

12 18

17 80

0 0

10 12

F

12

71

130

400

M

12

80

130

400

F

12 18 65

17 64 71

4.1 3.9 3.6

5.3 5.2 5.1

M

12 18 69

17 63 80

4.1 4.4 3.7

5.3 5.8 5.5

F

12

71

1.8

8

M

12

80

1.8

8

F

12

17

30

70

18

71

40

75

M

12 18

17 80

30 40

70 75

F

12

71

1.8

8

RM2008/00422/00

Segmented Neutrophils (percentage)

GI/L

F

CONFIDENTIAL

Platelet count

%

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 6 Table 8.23 Definitions of Normal Ranges for Laboratory Values

Age Range Normal Range _________ _____________ Lab Parameter Units Sex Low High Low High --------------------------------------------------------------------------Total Neutrophils GI/L M 12 80 1.8 8 Total Neutrophils (percentage)

917

IMMU Actin (smooth muscle) IgG antibody Cytomegalovirus IgM antibody Liver Kidney Microsomal Antibody IgG

12 18

17 71

30 40

70 75

M

12 18

17 80

30 40

70 75

F

12 18

17 71

4.5 3.8

13 10.8

M

12 18

17 80

4.5 3.8

13 10.8

UNITS

F

28

28

20

INDEX

F

28

28

0.8999

UNITS

F

28

28

20

ISR

F

28

28

0.91

GI/L

RM2008/00422/00

VIRO Epstein-Barr viral capsid antigen IgM antibody strength of signal

F

CONFIDENTIAL

White Blood Cell Count

%

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Chemistry Albumin (G/L) Placebo 155 Baseline 155 44.7 3.20 45.0 36 52 Week 4 147 44.1 2.93 44.0 35 51 Discontinuation 5 43.8 4.76 43.0 38 50 Endpoint 150 44.1 2.95 44.0 35 51 3.06 2.96 3.40 2.99

45.0 44.0 44.0 44.0

35 36 38 36

52 52 48 52

Placebo

155 Baseline Week 4 Discontinuation Endpoint

155 147 5 150

77.8 77.8 74.0 77.5

51.27 55.27 14.14 54.76

65.0 63.0 80.0 62.5

21 23 57 23

443 482 89 482

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 151 7 156

77.5 76.5 77.4 76.6

40.50 41.83 10.06 41.18

68.0 66.0 75.0 67.0

23 24 65 24

367 346 91 346

Alanine Amino Transferase (IU/L)

Placebo

155

18.9

14.38

16.0

5

127

Week 4 Discontinuation Endpoint

147 5 150

19.3 33.4 19.5

17.04 23.92 17.15

16.0 17.0 16.0

4 14 4

189 62 189

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 152 7 157

20.3 20.8 20.9 20.5

14.39 14.90 15.95 14.73

16.0 17.0 14.0 17.0

5 6 10 6

96 119 55 119

155 Baseline

RM2008/00422/00

44.5 44.1 44.3 44.1

918

159 151 7 156

CONFIDENTIAL

Alkaline Phosphatase (IU/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Aspartate Amino Transferase Placebo 155 Baseline 155 22.2 17.01 19.0 11 170 (IU/L) Week 4 147 23.0 27.90 19.0 11 343 Discontinuation 5 26.6 7.50 23.0 20 37 Endpoint 150 23.1 27.65 19.0 11 343 7.53 8.73 7.02 8.69

19.0 19.0 21.0 18.5

12 9 13 9

68 70 33 70

Placebo

155 Baseline Week 4 Discontinuation Endpoint

155 147 5 150

2.2 2.4 2.4 2.4

1.35 1.45 1.52 1.44

2.0 2.0 2.0 2.0

0 0 1 0

11 11 5 11

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 151 7 156

2.3 2.3 1.4 2.2

1.11 1.05 1.13 1.06

2.0 2.0 2.0 2.0

0 0 0 0

6 6 3 6

Total Bilirubin (UMOL/L)

Placebo

155 Baseline Week 4 Discontinuation Endpoint

155 147 5 150

10.1 10.6 11.6 10.5

6.17 6.44 8.68 6.39

8.0 8.0 8.0 8.0

2 4 6 4

53 44 27 44

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 151 7 156

9.7 9.7 7.7 9.7

4.70 4.53 3.09 4.50

8.0 8.0 6.0 8.0

3 4 4 4

30 28 13 28

RM2008/00422/00

20.7 20.8 20.6 20.7

919

159 151 7 156

CONFIDENTIAL

Direct Bilirubin (UMOL/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Calcium (MMOL/L) Placebo 155 Baseline 155 2.351 0.0770 2.350 2.18 2.51 Week 4 147 2.333 0.0891 2.320 2.13 2.60 Discontinuation 5 2.346 0.1122 2.360 2.18 2.49 Endpoint 150 2.333 0.0891 2.320 2.13 2.60 0.1032 0.1084 0.1152 0.1084

Glucose (MMOL/L)

2.340 2.340 2.320 2.340

2.14 2.14 2.18 2.14

3.03 3.19 2.50 3.19

Placebo

155 Baseline Week 4 Discontinuation Endpoint

155 147 5 150

76.7 77.3 90.2 77.4

13.51 12.79 10.16 12.70

74.0 74.0 88.0 76.5

44 44 80 44

122 118 104 118

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 151 7 156

77.2 78.0 78.3 78.0

13.54 13.61 17.88 13.51

76.0 77.0 80.0 77.0

39 40 53 40

132 125 106 125

Placebo

155 Baseline Week 4 Discontinuation Endpoint

155 147 5 150

5.35 5.40 5.20 5.38

1.392 1.657 0.731 1.644

5.10 5.10 5.70 5.10

3.4 2.3 4.4 2.3

14.5 15.9 5.8 15.9

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 152 7 157

5.15 5.28 6.91 5.36

1.408 1.168 5.688 1.634

5.00 5.15 4.80 5.10

2.7 2.1 4.3 2.1

19.9 12.1 19.8 19.8

RM2008/00422/00

2.353 2.350 2.321 2.350

920

159 152 7 157

CONFIDENTIAL

Creatinine (UMOL/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Potassium (MMOL/L) Placebo 155 Baseline 155 4.38 0.380 4.30 3.2 5.6 Week 4 147 4.28 0.320 4.20 3.5 5.2 Discontinuation 5 4.28 0.390 4.10 3.9 4.7 Endpoint 150 4.28 0.320 4.20 3.5 5.2 0.440 0.352 0.399 0.355

Total Protein (G/L)

4.30 4.30 4.10 4.30

3.4 3.6 3.9 3.6

5.9 5.3 5.1 5.3

Placebo

155 Baseline Week 4 Discontinuation Endpoint

155 147 5 150

140.2 140.0 140.2 140.0

1.81 1.68 1.48 1.68

140.0 140.0 140.0 140.0

136 136 138 136

146 144 142 144

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 152 7 157

140.3 140.2 139.4 140.2

1.96 2.09 2.51 2.10

140.0 140.0 140.0 140.0

135 135 136 135

147 149 143 149

Placebo

155 Baseline Week 4 Discontinuation Endpoint

155 147 5 150

71.8 70.6 73.4 70.6

4.31 3.90 4.83 3.92

72.0 71.0 75.0 71.0

62 62 65 62

82 81 77 81

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

159 151 7 156

71.8 71.4 72.9 71.4

3.82 3.92 4.10 3.92

72.0 72.0 73.0 72.0

64 60 66 60

82 82 78 82

RM2008/00422/00

4.34 4.32 4.23 4.32

921

159 152 7 157

CONFIDENTIAL

Sodium (MMOL/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Urea (MMOL/L) Placebo 155 Baseline 155 5.16 1.343 5.00 2.8 8.5 Week 4 147 5.03 1.378 5.00 2.0 10.5 Discontinuation 5 5.12 0.502 5.30 4.3 5.5 Endpoint 150 5.04 1.365 5.00 2.0 10.5 1.468 1.406 1.666 1.420

Basophils (percentage) (%)

5.00 5.00 5.00 5.00

2.0 1.5 2.6 1.5

Placebo

155 Baseline Week 4 Discontinuation Endpoint

154 147 5 150

0.022 0.024 0.018 0.024

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 151 6 156

Placebo

155 Baseline Week 4 Discontinuation Endpoint

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

10.5 11.1 7.0 11.1

0.0120 0.0110 0.0110 0.0110

0.020 0.020 0.020 0.020

0.00 0.00 0.00 0.00

0.06 0.07 0.03 0.07

0.025 0.023 0.020 0.023

0.0142 0.0137 0.0089 0.0136

0.020 0.020 0.020 0.020

0.00 0.00 0.01 0.00

0.07 0.07 0.03 0.07

154 147 5 150

0.35 0.39 0.34 0.39

0.204 0.179 0.195 0.177

0.30 0.40 0.40 0.40

0.0 0.1 0.0 0.1

1.6 1.1 0.5 1.1

160 152 7 157

0.38 0.36 0.27 0.36

0.214 0.208 0.160 0.205

0.40 0.30 0.30 0.30

0.0 0.0 0.0 0.0

1.3 1.2 0.5 1.2

RM2008/00422/00

5.02 5.07 4.91 5.06

922

159 151 7 156

CONFIDENTIAL

Hematology Basophils (GI/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Eosinophils (GI/L) Placebo 155 Baseline 154 0.215 0.1691 0.175 0.00 0.97 Week 4 147 0.209 0.1416 0.180 0.01 0.80 Discontinuation 5 0.258 0.1333 0.320 0.07 0.39 Endpoint 150 0.209 0.1409 0.175 0.01 0.80 0.227 0.202 0.305 0.207

0.1778 0.1423 0.2805 0.1499

155 Baseline Week 4 Discontinuation Endpoint

154 147 5 150

3.38 3.47 3.70 3.47

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 152 7 157

Placebo

155 Baseline Week 4 Discontinuation Endpoint

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Eosinophils (percentage) (%) Placebo

923 Hemoglobin (G/L)

0.180 0.180 0.235 0.180

0.01 0.02 0.09 0.02

1.17 0.80 0.84 0.84

2.621 2.313 1.849 2.300

2.75 2.90 3.00 2.90

0.0 0.2 1.5 0.2

15.4 12.4 6.0 12.4

3.49 3.24 4.17 3.29

2.615 2.311 3.769 2.396

2.90 2.80 3.00 2.80

0.2 0.2 1.3 0.2

18.3 12.7 12.4 12.7

154 147 5 150

136.6 134.4 142.0 134.4

11.52 11.81 18.59 11.87

136.0 133.0 140.0 133.5

102 105 115 105

178 168 166 168

160 151 6 156

137.3 136.4 128.2 136.0

11.90 11.94 12.04 12.04

137.0 136.0 125.0 136.0

101 106 113 106

163 163 144 163

RM2008/00422/00

160 151 6 156

CONFIDENTIAL

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Hematocrit (1) Placebo 155 Baseline 154 0.408 0.03385 0.407 0.33 0.52 Week 4 147 0.403 0.03603 0.400 0.31 0.52 Discontinuation 5 0.425 0.05117 0.420 0.35 0.49 Endpoint 150 0.403 0.03606 0.401 0.31 0.52 0.03421 0.03521 0.02559 0.03528

0.408 0.406 0.376 0.406

0.31 0.31 0.35 0.31

0.49 0.49 0.41 0.49

Placebo

155 Baseline Week 4 Discontinuation Endpoint

154 147 5 150

2.012 1.893 2.220 1.894

0.5793 0.5416 0.6732 0.5438

1.960 1.800 2.400 1.810

0.76 0.67 1.04 0.67

3.57 3.53 2.72 3.53

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 151 6 156

2.053 1.980 2.075 1.985

0.6089 0.6477 0.4097 0.6414

2.010 1.920 1.890 1.930

0.61 0.61 1.71 0.61

4.01 4.17 2.70 4.17

155 Baseline Week 4 Discontinuation Endpoint

154 147 5 150

31.60 31.21 35.10 31.30

7.851 8.051 16.292 8.259

30.65 31.20 38.50 31.35

9.6 6.8 16.8 6.8

60.2 61.3 52.2 61.3

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 152 7 157

31.58 31.75 30.77 31.72

8.429 8.806 7.557 8.789

30.75 31.40 32.50 31.40

10.8 8.9 17.8 8.9

52.1 52.9 39.2 52.9

Lymphocytes (percentage) (%) Placebo

RM2008/00422/00

0.409 0.410 0.384 0.409

924

160 151 6 156

CONFIDENTIAL

Lymphocytes (GI/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 8 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Monocytes (GI/L) Placebo 155 Baseline 154 0.347 0.1412 0.330 0.07 0.85 Week 4 147 0.329 0.1327 0.320 0.01 0.84 Discontinuation 5 0.396 0.0757 0.380 0.32 0.48 Endpoint 150 0.330 0.1318 0.320 0.01 0.84 0.1553 0.1661 0.0905 0.1642

Placebo

155 Baseline Week 4 Discontinuation Endpoint

154 147 5 150

5.54 5.45 6.10 5.47

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 152 7 157

155 Baseline Week 4 Discontinuation Endpoint

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Segmented Neutrophils (GI/L) Placebo

0.345 0.310 0.345 0.310

0.10 0.00 0.16 0.00

1.24 1.11 0.43 1.11

2.272 2.084 1.622 2.075

5.25 5.30 6.80 5.40

1.3 0.1 3.7 0.1

13.0 11.9 7.6 11.9

5.62 5.40 4.53 5.37

2.028 2.354 1.521 2.334

5.50 5.05 4.90 5.00

1.2 0.0 2.3 0.0

15.4 16.5 6.8 16.5

154 147 5 150

3.925 3.792 4.242 3.779

1.4340 1.4376 3.1960 1.4338

3.710 3.460 3.290 3.450

1.46 0.97 1.78 0.97

8.57 11.09 9.67 11.09

160 151 6 156

3.980 3.852 4.262 3.872

1.4130 1.4424 1.7486 1.4547

3.875 3.600 3.905 3.630

1.29 1.21 2.60 1.21

11.78 10.38 7.63 10.38

RM2008/00422/00

0.367 0.343 0.323 0.342

925

160 151 6 156

CONFIDENTIAL

Monocytes (percentage) (%)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 9 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Segmented Neutrophils Placebo 155 Baseline 154 59.13 9.396 59.75 30.6 87.4 (percentage) (%) Week 4 147 59.48 9.249 59.40 28.4 89.4 Discontinuation 5 54.76 16.758 53.10 38.3 73.8 Endpoint 150 59.37 9.365 59.35 28.4 89.4 9.445 9.888 7.655 9.835

Total Neutrophils (percentage) (%)

Placebo

155 Baseline Week 4 Discontinuation Endpoint

154 147 5 150

3.925 3.792 4.242 3.779

1.4340 1.4376 3.1960 1.4338

3.710 3.460 3.290 3.450

1.46 0.97 1.78 0.97

8.57 11.09 9.67 11.09

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 151 6 156

3.980 3.852 4.262 3.872

1.4130 1.4424 1.7486 1.4547

3.875 3.600 3.905 3.630

1.29 1.21 2.60 1.21

11.78 10.38 7.63 10.38

Placebo

154

59.13

9.396

59.75

30.6

87.4

Week 4 Discontinuation Endpoint

147 5 150

59.48 54.76 59.37

9.249 16.758 9.365

59.40 53.10 59.35

28.4 38.3 28.4

89.4 73.8 89.4

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 152 7 157

58.94 59.25 60.26 59.26

9.445 9.888 7.655 9.835

58.90 59.15 57.10 59.00

34.1 36.6 51.0 36.6

80.0 85.8 74.8 85.8

155 Baseline

58.90 59.15 57.10 59.00

34.1 36.6 51.0 36.6

80.0 85.8 74.8 85.8

RM2008/00422/00

58.94 59.25 60.26 59.26

926

160 152 7 157

CONFIDENTIAL

Total Neutrophils (GI/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 10 of 10 Table 8.24 Summary of Laboratory Values

Planned Lab category Relative Lab Parameter Treatment N Time n Mean SD Median Min Max -----------------------------------------------------------------------------------------------------------Platelet count (GI/L) Placebo 155 Baseline 152 267.1 63.49 263.0 76 617 Week 4 146 264.1 62.59 261.5 95 631 Discontinuation 5 269.2 46.34 261.0 203 321 Endpoint 149 264.7 62.22 262.0 95 631 60.12 59.12 96.88 60.77

White Blood Cell Count (GI/L)

Placebo

155 Baseline Week 4 Discontinuation Endpoint

154 147 5 150

4.52 4.46 4.86 4.47

0.438 0.445 0.513 0.445

4.50 4.40 4.80 4.40

3.7 3.6 4.1 3.6

7.0 7.1 5.5 7.1

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 151 6 156

4.55 4.54 4.42 4.54

0.430 0.440 0.256 0.436

4.50 4.50 4.40 4.50

3.6 3.6 4.1 3.6

6.7 6.8 4.7 6.8

Placebo

154

6.52

1.723

6.40

2.8

12.7

Week 4 Discontinuation Endpoint

147 5 150

6.25 7.14 6.24

1.672 3.395 1.660

6.00 6.20 6.05

3.4 4.6 3.4

12.4 13.1 12.4

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

160 151 6 156

6.65 6.40 6.98 6.43

1.654 1.712 1.806 1.717

6.60 6.20 6.85 6.30

2.2 2.5 5.1 2.5

14.8 12.1 10.2 12.1

155 Baseline

256.5 252.0 248.0 252.0

76 115 186 115

431 473 451 473

RM2008/00422/00

266.7 265.9 280.7 266.5

927

160 151 6 156

CONFIDENTIAL

Red Blood Cell Count (TI/L)

FF 110mcg QD 160 Baseline Week 4 Discontinuation Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Alanine Amino Transferase (IU/L) Baseline n 155 159 > Normal range 4 (3%) 7 (4%) n > Normal range

147 3

(2%)

152 9

(6%)

Discontinuation

n > Normal range

5 2

(40%)

7 1

(14%)

Endpoint

n > Normal range

150 4

(3%)

157 9

(6%)

Baseline

n > Normal range < Normal range

155 6 0

(4%)

159 4 0

(3%)

Week 4

n > Normal range < Normal range

147 2 0

(1%)

151 3 0

(2%)

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 2 0

CONFIDENTIAL

928

Albumin (G/L)

Week 4

7 0 0 156 3 0

(2%)

RM2008/00422/00

(1%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Alkaline Phosphatase (IU/L) Baseline n 155 159 > Normal range 4 (3%) 4 (3%) < Normal range 0 0 n > Normal range < Normal range

147 4 0

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 4 0

Baseline

n > Normal range

155 6

(4%)

159 4

(3%)

Week 4

n > Normal range

147 5

(3%)

151 3

(2%)

Discontinuation

n > Normal range

5 0

Endpoint

n > Normal range

150 5

(3%)

151 3 0

(2%)

7 0 0 (3%)

156 3 0

(2%)

CONFIDENTIAL

929 Aspartate Amino Transferase (IU/L)

Week 4

7 0 156 3

(2%)

RM2008/00422/00

(3%)

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Basophils (GI/L) Baseline n 154 160 > Normal range 0 0 n > Normal range

147 0

151 0

Discontinuation

n > Normal range

5 0

6 0

Endpoint

n > Normal range

150 0

156 0

Baseline

n > Normal range

154 0

160 0

Week 4

n > Normal range

147 0

152 0

Discontinuation

n > Normal range

5 0

7 0

Endpoint

n > Normal range

150 0

157 0

CONFIDENTIAL

930

Basophils (percentage) (%)

Week 4

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Calcium (MMOL/L) Baseline n 155 159 > Normal range 0 4 (3%) < Normal range 0 0 n > Normal range < Normal range

147 4 0

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 4 0

Baseline

n > Normal range < Normal range

155 0 0

159 1 1

(<1%) (<1%)

Week 4

n > Normal range < Normal range

147 0 0

151 1 1

(<1%) (<1%)

Discontinuation

n > Normal range < Normal range

5 0 0

7 0 0

Endpoint

n > Normal range < Normal range

150 0 0

156 1 1

(3%)

152 2 0

(1%)

7 0 0 (3%)

157 2 0

(1%)

RM2008/00422/00

(<1%) (<1%)

CONFIDENTIAL

931 Creatinine (UMOL/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Direct Bilirubin (UMOL/L) Baseline n 155 159 > Normal range 1 (<1%) 0 n > Normal range

147 2

Discontinuation

n > Normal range

5 0

Endpoint

n > Normal range

150 2

(1%)

156 0

Baseline

n > Normal range < Normal range

154 6 10

(4%) (6%)

160 7 9

(4%) (6%)

Week 4

n > Normal range < Normal range

147 4 7

(3%) (5%)

151 5 11

(3%) (7%)

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 4 7

(1%)

151 0 7 0

6 1 0 156 6 11

(17%)

(4%) (7%)

RM2008/00422/00

(3%) (5%)

CONFIDENTIAL

932

Eosinophils (GI/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Eosinophils (percentage) (%) Baseline n 154 160 > Normal range 13 (8%) 14 (9%) n > Normal range

147 13

152 11

(7%)

Discontinuation

n > Normal range

5 0

7 1

(14%)

Endpoint

n > Normal range

150 13

(9%)

157 12

(8%)

Baseline

n > Normal range < Normal range

155 14 3

(9%) (2%)

159 8 5

(5%) (3%)

Week 4

n > Normal range < Normal range

147 12 6

(8%) (4%)

152 11 6

(7%) (4%)

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 12 6

(9%)

7 1 0 157 12 6

(14%)

(8%) (4%)

RM2008/00422/00

(8%) (4%)

CONFIDENTIAL

933

Glucose (MMOL/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Hematocrit (1) Baseline n 154 160 > Normal range 4 (3%) 0 < Normal range 6 (4%) 11 (7%) n > Normal range < Normal range

147 2 14

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 2 14

(1%) (9%)

156 2 14

(1%) (9%)

Baseline

n > Normal range < Normal range

154 1 10

(<1%) (6%)

160 0 18

(11%)

n > Normal range < Normal range

147 0 16

(11%)

151 0 19

(13%)

n > Normal range < Normal range

5 0 1

(20%)

6 0 1

(17%)

n > Normal range < Normal range

150 0 17

(11%)

156 0 20

(13%)

Week 4

Discontinuation

151 2 14

(1%) (9%)

6 0 0

RM2008/00422/00

Endpoint

(1%) (10%)

CONFIDENTIAL

934 Hemoglobin (G/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 8 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Lymphocytes (GI/L) Baseline n 154 160 > Normal range 0 0 < Normal range 1 (<1%) 4 (3%) Week 4

147 0 2

Discontinuation

n > Normal range < Normal range

5 0 0

6 0 0

Endpoint

n > Normal range < Normal range

150 0 2

(1%)

156 2 3

(1%) (2%)

Baseline

n > Normal range < Normal range

154 3 2

(2%) (1%)

160 9 5

(6%) (3%)

Week 4

n > Normal range < Normal range

147 3 5

(2%) (3%)

152 7 7

(5%) (5%)

Discontinuation

n > Normal range < Normal range

5 2 0

Endpoint

n > Normal range < Normal range

150 4 5

(1%)

(3%) (3%)

(1%) (2%)

7 0 0 157 7 7

(4%) (4%)

RM2008/00422/00

(40%)

151 2 3

CONFIDENTIAL

935 Lymphocytes (percentage) (%)

n > Normal range < Normal range

Protocol: FFU111439 Population: Intent-to-Treat

Page 9 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Monocytes (GI/L) Baseline n 154 160 > Normal range 0 1 (<1%) < Normal range 22 (14%) 11 (7%) Week 4

936 Monocytes (percentage) (%)

n > Normal range < Normal range

5 0 0

6 0 1

(17%)

n > Normal range < Normal range

150 0 18

(12%)

156 1 27

(<1%) (17%)

Baseline

n > Normal range

154 1

(<1%)

160 1

(<1%)

Week 4

n > Normal range

147 0

152 2

(1%)

Discontinuation

n > Normal range

5 0

7 0

Endpoint

n > Normal range

150 0

157 2

(12%)

(1%)

RM2008/00422/00

(<1%) (17%)

Endpoint

147 0 18

CONFIDENTIAL

151 1 26

Discontinuation

n > Normal range < Normal range

Protocol: FFU111439 Population: Intent-to-Treat

Page 10 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Platelet count (GI/L) Baseline n 152 160 > Normal range 3 (2%) 3 (2%) < Normal range 2 (1%) 1 (<1%) n > Normal range < Normal range

146 3 1

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

149 3 1

(2%) (<1%)

156 6 1

(4%) (<1%)

Baseline

n > Normal range < Normal range

155 2 1

(1%) (<1%)

159 6 1

(4%) (<1%)

Week 4

n > Normal range < Normal range

147 0 0

152 0 0

Discontinuation

n > Normal range < Normal range

5 0 0

7 0 0

Endpoint

n > Normal range < Normal range

150 0 0

157 0 0

(2%) (<1%)

151 5 1 6 1 0

(3%) (<1%) (17%)

CONFIDENTIAL

937 Potassium (MMOL/L)

Week 4

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 11 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Red Blood Cell Count (TI/L) Baseline n 154 160 > Normal range 2 (1%) 2 (1%) < Normal range 6 (4%) 6 (4%) n > Normal range < Normal range

147 2 10

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 2 10

(1%) (7%)

156 2 10

(1%) (6%)

Baseline

n > Normal range < Normal range

154 2 7

(1%) (5%)

160 1 2

(<1%) (1%)

Week 4

n > Normal range < Normal range

147 1 5

(<1%) (3%)

151 3 3

(2%) (2%)

Discontinuation

n > Normal range < Normal range

5 1 1

(20%) (20%)

6 0 0

Endpoint

n > Normal range < Normal range

150 1 6

(<1%) (4%)

156 3 3

(1%) (7%)

151 2 10

(1%) (7%)

6 0 0

RM2008/00422/00

(2%) (2%)

CONFIDENTIAL

938 Segmented Neutrophils (GI/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 12 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Segmented Neutrophils (percentage) Baseline n 154 160 (%) > Normal range 6 (4%) 6 (4%) < Normal range 3 (2%) 3 (2%) n > Normal range < Normal range

147 5 2

(3%) (1%)

152 8 4

Discontinuation

n > Normal range < Normal range

5 0 2

(40%)

7 0 0

Endpoint

n > Normal range < Normal range

150 5 3

(3%) (2%)

157 8 4

Baseline

n > Normal range < Normal range

155 0 0

159 1 0

(<1%)

Week 4

n > Normal range < Normal range

147 0 0

152 1 0

(<1%)

Discontinuation

n > Normal range < Normal range

5 0 0

7 0 0

Endpoint

n > Normal range < Normal range

150 0 0

157 1 0

(5%) (3%)

(5%) (3%)

RM2008/00422/00

(<1%)

CONFIDENTIAL

939 Sodium (MMOL/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 13 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Total Bilirubin (UMOL/L) Baseline n 155 159 > Normal range 6 (4%) 4 (3%) n > Normal range

147 8

(5%)

151 4

Discontinuation

n > Normal range

5 1

(20%)

7 0

Endpoint

n > Normal range

150 8

(5%)

156 4

(3%)

Baseline

n > Normal range < Normal range

154 2 7

(1%) (5%)

160 1 2

(<1%) (1%)

Week 4

n > Normal range < Normal range

147 1 5

(<1%) (3%)

151 3 3

(2%) (2%)

Discontinuation

n > Normal range < Normal range

5 1 1

(20%) (20%)

6 0 0

Endpoint

n > Normal range < Normal range

150 1 6

(<1%) (4%)

156 3 3

(3%)

RM2008/00422/00

(2%) (2%)

CONFIDENTIAL

940

Total Neutrophils (GI/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 14 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Total Neutrophils (percentage) (%) Baseline n 154 160 > Normal range 6 (4%) 6 (4%) < Normal range 3 (2%) 3 (2%) n > Normal range < Normal range

147 5 2

152 8 4

Discontinuation

n > Normal range < Normal range

5 0 2

(40%)

7 0 0

Endpoint

n > Normal range < Normal range

150 5 3

(3%) (2%)

157 8 4

Baseline

n > Normal range < Normal range

155 0 0

159 0 0

Week 4

n > Normal range < Normal range

147 0 0

151 0 0

Discontinuation

n > Normal range < Normal range

5 0 0

7 0 0

Endpoint

n > Normal range < Normal range

150 0 0

156 0 0

(5%) (3%)

(5%) (3%)

RM2008/00422/00

(3%) (1%)

CONFIDENTIAL

941 Total Protein (G/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 15 of 15 Table 8.25 Summary of Laboratory Data Outside the Normal Range

Planned Relative Normal Range Placebo FF 110mcg QD Lab Test Time Category (N=155) (N=160) --------------------------------------------------------------------------------------------------Urea (MMOL/L) Baseline n 155 159 > Normal range 0 2 (1%) < Normal range 0 2 (1%) n > Normal range < Normal range

147 3 1

Discontinuation

n > Normal range < Normal range

5 0 0

Endpoint

n > Normal range < Normal range

150 3 1

(2%) (<1%)

156 2 4

(1%) (3%)

Baseline

n > Normal range < Normal range

154 2 4

(1%) (3%)

160 1 3

(<1%) (2%)

Week 4

n > Normal range < Normal range

147 2 6

(1%) (4%)

151 2 4

(1%) (3%)

Discontinuation

n > Normal range < Normal range

5 1 0

Endpoint

n > Normal range < Normal range

150 2 6

(2%) (<1%)

151 2 4

(1%) (3%)

7 0 0

(1%) (4%)

6 0 0 156 2 4

(1%) (3%)

RM2008/00422/00

(20%)

CONFIDENTIAL

942 White Blood Cell Count (GI/L)

Week 4

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 6 Table 8.26 Summary of Laboratory Shifts from Baseline to Endpoint

Placebo FF 110mcg QD Shift from Baseline (N=155) (N=160) -------------------------------------------------------------------------------Chemistry Albumin n 150 155 To Low 0 0 To Normal or No Change 148 (99%) 152 (98%) To High 2 (1%) 3 (2%) 155 0 155 (100%) 0

Alanine Amino Transferase n To Low To Normal or No Change To High

150 0 149 (>99%) 1 (<1%)

156 0 153 3

(98%) (2%)

Aspartate Amino Transferase n To Low To Normal or No Change To High

150 0 148 2

155 0 153 2

(99%) (1%)

Direct Bilirubin n To Low To Normal or No Change To High

150 0 149 (>99%) 1 (<1%)

(99%) (1%)

155 0 155 (100%) 0

RM2008/00422/00

150 0 150 (100%) 0

CONFIDENTIAL

943

Alkaline Phosphatase n To Low To Normal or No Change To High

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 6 Table 8.26 Summary of Laboratory Shifts from Baseline to Endpoint

Placebo FF 110mcg QD Shift from Baseline (N=155) (N=160) -------------------------------------------------------------------------------Total Bilirubin n 150 155 To Low 0 0 To Normal or No Change 147 (98%) 153 (99%) To High 3 (2%) 2 (1%) 150 0 146 4

(97%) (3%)

156 0 155 (>99%) 1 (<1%)

Creatinine n To Low To Normal or No Change To High

150 0 150 (100%) 0

155 0 154 (>99%) 1 (<1%)

Glucose n To Low To Normal or No Change To High

150 6 140 4

156 5 141 10

Potassium n To Low To Normal or No Change To High

150 0 150 (100%) 0

(4%) (93%) (3%)

CONFIDENTIAL

944

Calcium n To Low To Normal or No Change To High

(3%) (90%) (6%)

RM2008/00422/00

156 0 156 (100%) 0

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 6 Table 8.26 Summary of Laboratory Shifts from Baseline to Endpoint

Placebo FF 110mcg QD Shift from Baseline (N=155) (N=160) -------------------------------------------------------------------------------Sodium n 150 156 To Low 0 0 To Normal or No Change 150 (100%) 155 (>99%) To High 0 1 (<1%) 150 0 150 (100%) 0

155 0 155 (100%) 0

Urea n To Low To Normal or No Change To High

150 1 146 3

155 2 151 2

(<1%) (97%) (2%)

(1%) (97%) (1%)

149 0 149 (100%) 0

156 0 156 (100%) 0

Basophils (percentage) n To Low To Normal or No Change To High

149 0 149 (100%) 0

157 0 157 (100%) 0

RM2008/00422/00

Hematology Basophils n To Low To Normal or No Change To High

CONFIDENTIAL

945

Total Protein n To Low To Normal or No Change To High

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 6 Table 8.26 Summary of Laboratory Shifts from Baseline to Endpoint

Placebo FF 110mcg QD Shift from Baseline (N=155) (N=160) -------------------------------------------------------------------------------Eosinophils n 149 156 To Low 5 (3%) 5 (3%) To Normal or No Change 142 (95%) 148 (95%) To High 2 (1%) 3 (2%)

Hemoglobin n To Low To Normal or No Change To High

149 10 139 0

Hematocrit n To Low To Normal or No Change To High

149 10 138 1

(7%) (93%) (<1%)

156 7 147 2

(4%) (94%) (1%)

Lymphocytes n To Low To Normal or No Change To High

149 1 (<1%) 148 (>99%) 0

156 1 153 2

(<1%) (98%) (1%)

(96%) (4%)

(7%) (93%)

157 0 152 5 156 8 148 0

(97%) (3%)

(5%) (95%)

RM2008/00422/00

149 0 143 6

CONFIDENTIAL

946

Eosinophils (percentage) n To Low To Normal or No Change To High

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 6 Table 8.26 Summary of Laboratory Shifts from Baseline to Endpoint

Placebo FF 110mcg QD Shift from Baseline (N=155) (N=160) -------------------------------------------------------------------------------Lymphocytes (percentage) n 149 157 To Low 4 (3%) 5 (3%) To Normal or No Change 141 (95%) 151 (96%) To High 4 (3%) 1 (<1%)

Monocytes (percentage) n To Low To Normal or No Change To High

149 0 149 (100%) 0

157 0 156 (>99%) 1 (<1%)

Segmented Neutrophils n To Low To Normal or No Change To High

149 3 145 1

(2%) (97%) (<1%)

156 2 151 3

(1%) (97%) (2%)

Segmented Neutrophils (percentage) n To Low To Normal or No Change To High

149 3 143 3

(2%) (96%) (2%)

157 2 148 7

(1%) (94%) (4%)

(7%) (93%)

156 19 136 1

(12%) (87%) (<1%)

RM2008/00422/00

149 10 139 0

CONFIDENTIAL

947

Monocytes n To Low To Normal or No Change To High

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 6 Table 8.26 Summary of Laboratory Shifts from Baseline to Endpoint

Placebo FF 110mcg QD Shift from Baseline (N=155) (N=160) -------------------------------------------------------------------------------Total Neutrophils n 149 156 To Low 3 (2%) 2 (1%) To Normal or No Change 145 (97%) 151 (97%) To High 1 (<1%) 3 (2%) 149 3 143 3

(2%) (96%) (2%)

157 2 148 7

(1%) (94%) (4%)

Platelet count n To Low To Normal or No Change To High

147 0 146 (>99%) 1 (<1%)

156 0 152 4

(97%) (3%)

Red Blood Cell Count n To Low To Normal or No Change To High

149 5 144 0

156 4 152 0

White Blood Cell Count n To Low To Normal or No Change To High

149 5 143 1

(3%) (97%)

156 3 151 2

(3%) (97%)

(2%) (97%) (1%)

RM2008/00422/00

(3%) (96%) (<1%)

CONFIDENTIAL

948

Total Neutrophils (percentage) n To Low To Normal or No Change To High

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 252

Table 8.27 Listing of Laboratory Data for Subjects with at Least One Abnormal Value Post-Randomization in Hematology

Treatment: Placebo Age(y)/ Inv./ Sex/ Subj. Race

Lab date Visit

Parameter

Study Day

Lab Flag value [1]

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

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[1]L = Below normal range; H = Above normal range; I = Within normal range.

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 107

Table 8.28 Listing of Laboratory Data for Subjects with at Least One Abnormal Value Post-Randomization in Chemistry

Treatment: Placebo Age(y)/ Inv./ Sex/ Study Lab Flag Subj. Race Lab date Visit Parameter Day value [1] ----------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

1201

RM2008/00422/00

[1]L = Below normal range; H = Above normal range; I = Within normal range.

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 3 Table 8.29 Summary of Nasal Examinations

Placebo FF 110mcg QD Visit (N=155) (N=160) -----------------------------------------------------------------------------------------------Mucosa Bleeding Screening 155 160 Absent 152 (98%) 157 (98%) Present 3 (2%) 3 (2%) 160 156 (98%) 4 (3%)

Week 1 Absent Present

152 150 (99%) 2 (1%)

158 153 (97%) 5 (3%)

Week 2 Absent Present

151 146 (97%) 5 (3%)

157 150 (96%) 7 (4%)

Week 3 Absent Present

148 143 (97%) 5 (3%)

153 143 (93%) 10 (7%)

Week 4 Absent Present

148 147(>99%) 1 (<1%)

153 144 (94%) 9 (6%)

6 5 (83%) 1 (17%)

7 7(100%) 0

Disc. Visit Absent Present

RM2008/00422/00

155 153 (99%) 2 (1%)

CONFIDENTIAL

1308

Visit 2/Rand Absent Present

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 3 Table 8.29 Summary of Nasal Examinations

Placebo FF 110mcg QD Visit (N=155) (N=160) -----------------------------------------------------------------------------------------------Ulcers Turbinates/Septum Screening 155 160 None 155(100%) 158 (99%) Small/Large 0 2 (1%) 160 159(>99%) 1 (<1%)

Week 1 None Small/Large

152 149 (98%) 3 (2%)

158 156 (99%) 2 (1%)

Week 2 None Small/Large

151 150(>99%) 1 (<1%)

157 154 (98%) 3 (2%)

Week 3 None Small/Large

148 147(>99%) 1 (<1%)

153 150 (98%) 3 (2%)

Week 4 None Small/Large

148 148(100%) 0

153 151 (99%) 2 (1%)

Disc. Visit None Small/Large

6 6(100%) 0

7 7(100%) 0

RM2008/00422/00

155 154(>99%) 1 (<1%)

CONFIDENTIAL

1309

Visit 2/Rand None Small/Large

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 3 Table 8.29 Summary of Nasal Examinations

Placebo FF 110mcg QD Visit (N=155) (N=160) -----------------------------------------------------------------------------------------------Polyposis Turbinates/Septum Screening 155 160 None 154(>99%) 157 (98%) Small/Large 1 (<1%) 3 (2%) 160 155 (97%) 5 (3%)

Week 1 None Small/Large

152 152(100%) 0

158 155 (98%) 3 (2%)

Week 2 None Small/Large

151 149 (99%) 2 (1%)

157 152 (97%) 5 (3%)

Week 3 None Small/Large

148 147(>99%) 1 (<1%)

153 149 (97%) 4 (3%)

Week 4 None Small/Large

148 147(>99%) 1 (<1%)

153 149 (97%) 4 (3%)

Disc. Visit None Small/Large

6 6(100%) 0

7 7(100%) 0

RM2008/00422/00

155 153 (99%) 2 (1%)

CONFIDENTIAL

1310

Visit 2/Rand None Small/Large

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.30 Summary of Nasal Examination Shifts from Baseline to Endpoint

Placebo FF 110mcg QD (N=155) (N=160) -------------------------------------------------------------------------------Mucosa Bleeding 154 160 Improved 3 (2%) 3 (2%) No Change 149 (97%) 148 (93%) Worsened 2 (1%) 9 (6%) 154 0 154(100%) 0

160 2 (1%) 156 (98%) 2 (1%)

Polyposis Turbinates/Septum Improved No Change Worsened

154 0 154(100%) 0

160 0 159(>99%) 1 (<1%)

RM2008/00422/00

Improved=shift from present for any nostril at baseline to absent for both nostrils at endpoint Worsened=shift from absent for both nostrils at baseline to present for any nostril at endpoint

CONFIDENTIAL

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Ulcers Turbinates/Septum Improved No Change Worsened

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 15

Table 8.31 Listing of Subjects with at least one Occurrence of Worsening Ulcers at any time Post-Baseline

Treatment: Placebo Invid/ Age/ Visit Result Subjid Sex Race Desc. Parameter (Left, Right) -----------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

1312

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 44

Table 8.32 Listing of Subjects with at least one Occurrence of Worsening Mucosal Bleeding at any time Post-Baseline

Treatment: Placebo Invid/ Age/ Visit Result Subjid Sex Race Desc. Parameter (Left, Right) -----------------------------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

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RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 56

Table 8.33 Listing of Subjects with at Least One Abnomal Nasal Examination Result Post-Baseline

Treatment: Placebo Invid/ Age/ Subjid Sex Race

Visit Desc.

Parameter

Result (Left, Right)

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

1371

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.34 Listing of Subjects With Clinical Evidence of Nasal Candidiasis

Clinical Inv./ Age (yr)/ Evidence of Treatment Subj. Sex Visit Candidiasis Result ----------------------------------------------------------------------------------------This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

CONFIDENTIAL

1427

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2 Table 8.35 Summary of Vitals Signs

Placebo FF 110mcg QD (N=155) (N=160) ------------------------------------------------------------------------------------Systolic BP (mmHg) Screening n 155 159 Mean 119.7 120.6 SD 14.08 15.62 Median 120.0 120.0 Min. 90 83 Max. 178 182 154 117.8 13.16 118.0 90 156

160 117.6 13.36 116.0 88 164

Screening

n Mean SD Median Min. Max.

155 76.8 9.96 78.0 57 107

159 78.5 11.01 78.0 54 110

Endpoint

n Mean SD Median Min. Max.

154 76.3 10.41 78.0 42 108

160 76.5 10.32 76.0 51 108

RM2008/00422/00

n Mean SD Median Min. Max.

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1428

Diastolic BP (mmHg)

Endpoint

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2 Table 8.35 Summary of Vitals Signs

Placebo FF 110mcg QD (N=155) (N=160) ------------------------------------------------------------------------------------Heart Rate (beats/min) Screening n 155 159 Mean 73.7 72.3 SD 10.24 8.91 Median 72.0 72.0 Min. 47 54 Max. 103 102 Endpoint

154 73.8 10.00 73.0 50 116

160 74.1 9.68 72.0 48 111

CONFIDENTIAL

1429

n Mean SD Median Min. Max.

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 1

Table 8.36 Summary of Change from Baseline in Vital Signs at Endpoint Placebo FF 110mcg QD (N=155) (N=160) -------------------------------------------------------Systolic BP (mmHg) n 154 159 Mean -2.0 -3.0 SD 12.25 9.94 Median 0.0 -2.0 Min. -50 -30 Max. 22 26 n Mean SD Median Min. Max.

154 -0.6 8.72 0.0 -37 25

159 -2.0 7.50 -2.0 -24 24

Heart Rate (beats/min)

n Mean SD Median Min. Max.

154 0.1 8.36 0.0 -25 24

159 1.6 8.55 1.0 -28 31

CONFIDENTIAL

1430

Diastolic BP (mmHg)

RM2008/00422/00

CONFIDENTIAL

RM2008/00422/00

Heath Outcome Data Source Tables Page

Table 9.1 Summary of RQLQ(S) Scores (Intent-to-Treat Population). . . . . . .

1432

Table 9.2 Analysis of Mean Change from Baseline to Endpoint in RQLQ(S) Scores (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Overall Baseline n 153 156 Mean (SD) 3.8(1.0) 3.5(1.1) Median 3.8 3.5 Min - Max 1.3 - 5.7 0.2 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

150 2.5(1.4) 2.3 0.0 - 6.0

158 1.9(1.4) 1.5 0.0 - 5.2

148 -1.3(1.4) -1.0 -4.4 - 1.1

154 -1.6(1.5) -1.5 -5.4 - 2.9

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Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Activities Baseline n 153 150 Mean (SD) 3.8(1.1) 3.7(1.3) Median 4.0 4.0 Min - Max 1.0 - 6.0 0.0 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

149 2.6(1.6) 2.3 0.0 - 6.0

155 2.0(1.5) 1.7 0.0 - 5.3

147 -1.2(1.6) -1.0 -5.0 - 2.3

147 -1.6(1.7) -1.7 -6.0 - 3.0

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1433

Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 3 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Sleep Baseline n 153 150 Mean (SD) 3.8(1.3) 3.6(1.6) Median 4.0 3.7 Min - Max 0.7 - 6.0 0.0 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

149 2.4(1.8) 2.3 0.0 - 6.0

156 1.7(1.6) 1.0 0.0 - 6.0

147 -1.4(1.7) -1.0 -5.3 - 3.0

147 -1.8(1.8) -1.7 -6.0 - 1.3

CONFIDENTIAL

1434

Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 4 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Non-Nose/Eye Symptoms Baseline n 151 157 Mean (SD) 3.5(1.3) 3.1(1.4) Median 3.4 3.1 Min - Max 0.0 - 5.9 0.3 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

149 2.4(1.5) 2.3 0.0 - 6.0

158 1.7(1.4) 1.4 0.0 - 5.0

145 -1.1(1.5) -0.9 -4.6 - 2.3

155 -1.4(1.5) -1.3 -5.6 - 2.6

CONFIDENTIAL

1435

Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 5 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Practical Problems Baseline n 151 157 Mean (SD) 4.5(1.2) 4.2(1.4) Median 4.7 4.3 Min - Max 1.0 - 6.0 0.0 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

150 2.9(1.8) 3.0 0.0 - 6.0

155 2.3(1.7) 2.0 0.0 - 6.0

146 -1.5(1.6) -1.3 -5.7 - 2.0

152 -1.9(1.9) -1.7 -6.0 - 3.0

CONFIDENTIAL

1436

Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 6 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Nasal Symptoms Baseline n 154 155 Mean (SD) 4.3(1.0) 4.1(1.2) Median 4.3 4.3 Min - Max 1.5 - 6.0 0.3 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

150 2.8(1.5) 2.8 0.0 - 6.0

158 2.2(1.6) 2.0 0.0 - 6.0

149 -1.5(1.5) -1.3 -5.0 - 1.8

153 -1.9(1.7) -1.8 -6.0 - 3.0

CONFIDENTIAL

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Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 7 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Eye Symptoms Baseline n 155 157 Mean (SD) 3.9(1.2) 3.5(1.3) Median 4.0 3.8 Min - Max 1.0 - 6.0 0.3 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

150 2.4(1.6) 2.4 0.0 - 6.0

158 1.9(1.5) 1.8 0.0 - 5.8

150 -1.4(1.7) -1.0 -5.5 - 1.5

155 -1.6(1.7) -1.5 -5.8 - 4.3

CONFIDENTIAL

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Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 8 of 8 Table 9.1 Summary of RQLQ(S) Scores

FF 110mcg Placebo QD (N=155) (N=160) -----------------------------------------------------------------Emotional Baseline n 151 158 Mean (SD) 3.4(1.4) 3.2(1.5) Median 3.5 3.3 Min - Max 0.0 - 6.0 0.0 - 6.0

Change from Baseline to Endpoint n Mean (SD) Median Min - Max

149 2.1(1.7) 2.0 0.0 - 6.0

157 1.6(1.5) 1.3 0.0 - 6.0

147 -1.3(1.6) -1.0 -5.8 - 2.0

155 -1.6(1.7) -1.3 -5.8 - 3.8

CONFIDENTIAL

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Endpoint (Week 6 or Discontinuation) n Mean (SD) Median Min - Max

RM2008/00422/00

Protocol: FFU111439 Population: Intent-to-Treat

Page 1 of 2

Table 9.2 Analysis of Mean Change from Baseline to Endpoint in RQLQ(S) Scores

Placebo FF 110mcg QD (N=155) (N=160) -------------------------------------------------------------------------------Overall n 148 154 LS Mean, Std Err -1.22 (0.18) -1.76 (0.16) LS Mean Difference -0.537 p-value vs. Placebo 0.028 95% C.I. (-1.01,-0.06)

Sleep n LS Mean, Std Err LS Mean Difference p-value vs. Placebo 95% C.I.

147 -1.78 (0.18) -0.595 0.028 (-1.13,-0.06)

147 -1.24 (0.22)

147 -1.99 (0.19) -0.751 0.010 (-1.32,-0.18)

145 -0.91 (0.19)

155 -1.53 (0.16) -0.614 0.014 (-1.10,-0.13)

RM2008/00422/00

Non-Nose/Eye Symptoms n LS Mean, Std Err LS Mean Difference p-value vs. Placebo 95% C.I.

147 -1.18 (0.20)

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Activities n LS Mean, Std Err LS Mean Difference p-value vs. Placebo 95% C.I.

Protocol: FFU111439 Population: Intent-to-Treat

Page 2 of 2

Table 9.2 Analysis of Mean Change from Baseline to Endpoint in RQLQ(S) Scores

Placebo FF 110mcg QD (N=155) (N=160) -------------------------------------------------------------------------------Practical Problems n 146 152 LS Mean, Std Err -1.46 (0.23) -2.03 (0.19) LS Mean Difference -0.569 p-value vs. Placebo 0.058 95% C.I. (-1.16, 0.02)

Eye Symptoms n LS Mean, Std Err LS Mean Difference p-value vs. Placebo 95% C.I.

153 -2.07 (0.18) -0.592 0.031 (-1.13,-0.05)

150 -1.42 (0.21)

155 -1.79 (0.18) -0.374 0.174 (-0.91, 0.17)

147 -1.15 (0.21)

155 -1.63 (0.17) -0.480 0.077 (-1.01, 0.05)

RM2008/00422/00

Emotional n LS Mean, Std Err LS Mean Difference p-value vs. Placebo 95% C.I.

149 -1.48 (0.21)

CONFIDENTIAL

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Nasal Symptoms n LS Mean, Std Err LS Mean Difference p-value vs. Placebo 95% C.I.

RM2008/00422/00

CONFIDENTIAL

CONFIDENTIAL The GlaxoSmithKline group of companies

RM2008/00335/00 FFU111439

Division: World Wide Development Retention Category: GRS019 Information Type: Reporting and Analysis Plan Title:

Reporting and Analysis Plan for FFU111439: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR)

Compound Number: GW685698 Effective Date:

13-JUNE-2008

Description: Identifier/Version Number: RM2008/00335/00 Subject: GW685698X, Perennial Allergic Rhinitis Author’s Name, Title and Functional Area:

Approved by:

Name Title Functional Area

Date

Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

1

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CONFIDENTIAL

RM2008/00422/00

RM2008/00335/00 FFU111439

TABLE OF CONTENTS PAGE ABBREVIATIONS ...........................................................................................................4 1.

INTRODUCTION......................................................................................................5

2.

STUDY OBJECTIVE(S) AND ENDPOINT(S) ...........................................................5 2.1. Study Objective(s) ........................................................................................5 2.2. Study Endpoint(s) .........................................................................................5 2.2.1. Efficacy Endpoints .........................................................................5 2.2.1.1. Primary efficacy endpoint .............................................5 2.2.1.2. Key Secondary efficacy endpoints................................5 2.2.1.3. Other Secondary efficacy endpoints .............................6 2.2.2. Safety Endpoints............................................................................7 2.2.3. Health Outcomes Endpoint ............................................................7 2.3. Statistical Hypotheses...................................................................................7

3.

STUDY DESIGN ......................................................................................................8

4.

PLANNED ANALYSES ............................................................................................9 4.1. Interim Analyses ...........................................................................................9

5.

SAMPLE SIZE CONSIDERATIONS .........................................................................9

6.

ANALYSIS POPULATIONS ...................................................................................10

7.

TREATMENT COMPARISONS..............................................................................10 7.1. Data Display Treatment and Other Sub-group Descriptors .........................10

8.

GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................10 8.1. Multicentre Studies .....................................................................................11 8.2. Other Strata and Covariates .......................................................................11 8.3. Examination of Subgroups..........................................................................11 8.4. Multiple Comparisons and Multiplicity ......................................................... 11

9.

DATA HANDLING CONVENTIONS .......................................................................12 9.1. Premature Withdrawal and Missing Data ....................................................12 9.2. Derived and Transformed Data...................................................................12 9.2.1. Calculation of Days on Treatment................................................12 9.2.2. Calculation of Baseline, Treatment Period, and Weekly Means for Symptom Scores......................................................... 13 9.2.3. Calculation of Total Nasal Symptom Scores and Total Ocular Symptom Scores ..............................................................13 9.2.4. Calculation of Change from Baseline and Percent Change from Baseline...............................................................................14 9.2.5. Calculation of Treatment Compliance .......................................... 14 9.2.6. Determination of Extent of Exposure to Study Medication............ 14 9.2.7. Calculation of Adverse Event Duration and Time to Onset of Adverse Event .........................................................................14

2

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9.2.8. 9.3.

Scoring of the Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities .................................. 15 Assessment Windows.................................................................................16

10. STUDY POPULATION ...........................................................................................16 10.1. Disposition of Subjects................................................................................16 10.2. Protocol Deviations.....................................................................................17 10.3. Demographic and Baseline Characteristics.................................................17 10.4. Concomitant Medications............................................................................17 10.5. Treatment Compliance................................................................................18 11. EFFICACY ANALYSES..........................................................................................18 11.1. Primary Efficacy Analysis(es)......................................................................19 11.2. Secondary Efficacy Analysis(es).................................................................19 11.2.1. Key Secondary Efficacy Analyses................................................20 11.2.1.1. Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score................20 11.2.1.2. Mean Change from Baseline in daily reflective Total Ocular Symptom Score......................................20 11.2.2. Other Secondary Efficacy Analyses ............................................. 20 11.2.2.1. Total Nasal Symptoms ...............................................20 11.2.2.2. Individual Nasal Symptoms ........................................21 11.2.2.3. Total Ocular Symptoms ..............................................22 11.2.2.4. Individual Ocular Symptoms .......................................22 11.2.2.5. Time to Onset of Treatment Effect..............................23 11.2.2.6. Time to Maximum Effect .............................................23 12. SAFETY ANALYSES .............................................................................................24 12.1. Extent of Exposure .....................................................................................24 12.2. Adverse Events...........................................................................................24 12.3. Deaths and Serious Adverse Events........................................................... 25 12.4. Pregnancies (as applicable)........................................................................ 25 12.5. Clinical Laboratory Evaluations...................................................................25 12.6. Other Safety Measures ...............................................................................26 12.6.1. Nasal Examination.......................................................................26 12.6.2. Vital Signs....................................................................................27 13. HEALTH OUTCOMES ANALYSES ........................................................................27 13.1. Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities .....................................................................................................27 14. PHARMACOGENETIC DATA ANALYSES.............................................................27 15. REFERENCES.......................................................................................................28 16. ATTACHMENTS ....................................................................................................29 16.1. Table of Contents for Data Display Specifications....................................... 29 16.2. Data Display Specifications ........................................................................ 39

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ABBREVIATIONS AE AM ANCOVA ATC CRF CSR ECG GSK IDSL iTNSS iTOSS ITT MedDRA PM RandAll RAP RQLQ (S) rTNSS rTOSS PAR SOC TNSS TOSS

Adverse Event Morning Analysis of Covariance Anatomical-Therapeutical-Chemical Case Report Form Clinical Study Report Electrocardiogram GlaxoSmithKline International Data Standards Library Instantaneous, Total Nasal Symptom Score Instantaneous, Total Ocular Symptom Score Intent-to-Treat Medical Dictionary for Regulatory Activities Evening GSK’s web server-based clinical trials randomization system Reporting and Analysis Plan Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities Reflective, Total Nasal Symptom Score Reflective, Total Ocular Symptom Score Perennial Allergic Rhinitis System Organ Class Total Nasal Symptom Score Total Ocular Symptom Score

Trademark Information Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

None

SAS UNIX

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INTRODUCTION

This Reporting and Analysis Plan (RAP) prospectively defines and documents the statistical methods to be used and the analyses required for the clinical study report of protocol FFU111439, a randomized, double-blind, placebo-controlled, parallel-group, multicenter, study to evaluate the efficacy and safety of once daily, intranasal administration of fluticasone furoate nasal spray (FFNS) 110mcg for 4 weeks in adult and adolescent subjects with perennial allergic rhinitis (PAR). All decisions regarding analysis, as defined in this document, have been made prior to unblinding of the study data.

2.

STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1.

Study Objective(s)

The objective of this study is to compare the efficacy and safety of FFNS 110mcg with vehicle placebo nasal spray in adult and adolescent subjects ≥ 12 years with perennial allergic rhinitis (PAR).

2.2.

Study Endpoint(s)

All primary and secondary efficacy endpoints are based on subjects’ ratings of their rhinitis symptoms. 2.2.1.

Efficacy Endpoints

2.2.1.1.

Primary efficacy endpoint

The primary efficacy endpoint will be the mean change from baseline over the entire treatment period in daily, reflective, total nasal symptom score (rTNSS). The TNSS is equal to the sum of the scores for rhinorrhea, nasal congestion, nasal itching and sneezing. 2.2.1.2.

Key Secondary efficacy endpoints

•

Mean change from baseline over the entire treatment period in morning (AM), predose, instantaneous, total nasal symptom score (iTNSS).

•

Mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS)

The TOSS is equal to the sum of the scores for itching/burning eyes, tearing/watering eyes, and eye redness.

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Other Secondary efficacy endpoints

Total Nasal Symptoms

•

Mean change from baseline over the entire treatment period in AM rTNSS

•

Mean change from baseline over the entire treatment period in PM rTNSS

•

Mean percent change from baseline over the entire treatment period in daily rTNSS

•

Mean percent change from baseline over the entire treatment period in AM, predose iTNSS

Individual Nasal Symptoms

•

Mean change from baseline over the entire treatment period in daily, reflective individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline over the entire treatment period in AM, pre-dose, instantaneous individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline over the entire treatment period in AM, reflective individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline over the entire treatment period in PM, reflective individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

Total Ocular Symptoms

•

Mean change from baseline over the entire treatment period in AM, pre-dose iTOSS

•

Mean change from baseline over the entire treatment period in AM rTOSS

•

Mean change from baseline over the entire treatment period in PM rTOSS

•

Mean percent change from baseline over the entire treatment period in daily rTOSS

•

Mean percent change from baseline over the entire treatment period in AM, predose iTOSS

Individual Ocular Symptoms

•

Mean change from baseline over the entire treatment period in daily, reflective individual symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

Mean change from baseline over the entire treatment period in AM, pre-dose, instantaneous individual symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

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•

Mean change from baseline over the entire treatment period in AM, reflective individual symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

Mean change from baseline over the entire treatment period in PM, reflective individual symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

Peak Nasal Inspiratory Flow (PNIF)

•

Mean change from baseline over the entire treatment period in daily peak nasal inspiratory flow (PNIF)

•

Mean change from baseline over the entire treatment period in AM peak nasal inspiratory flow

•

Mean change from baseline over the entire treatment period in PM peak nasal inspiratory flow

The PNIF is an objective measure of nasal airflow obstruction. 2.2.2.

Safety Endpoints

Safety endpoints for the study are: •

Frequency and type of clinical adverse events

•

Results of clinical laboratory tests (haematology and chemistry)

•

Nasal examination (mucosal bleeding, ulcers, polyps, and fungal infections)

•

Vital signs (systolic and diastolic blood pressure, and heart rate [pulse]).

2.2.3.

Health Outcomes Endpoint

The health outcomes endpoint will be the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) with Standardized Activities [RQLQ(S)].

2.3.

Statistical Hypotheses

The purpose of this study is to compare the safety and efficacy of FFNS 110mcg with vehicle placebo nasal spray. The hypothesis that corresponds to the primary and secondary analyses is: H0: µ100 = µPBO HA: µ100 ≠ µPBO where µ100 and µPBO represent the mean change (or percent change) from baseline over the entire treatment period on efficacy measures for the FFNS 110mcg and vehicle placebo nasal spray treatment groups, respectively.

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STUDY DESIGN

This is a multicenter, double-blind, randomized, parallel-group, placebo-controlled trial, multicenter study to be conducted in North America and Europe. Approximately 40 - 50 investigative sites will randomize approximately 288 subjects. Subjects will record their symptom assessment scores on electronic diaries corresponding to the phase of the study. All subjects will be outpatients. Clinic visits will be scheduled to occur at the following intervals: Visit 1 Screening (7 to 14 days prior to Randomization) Visit 2 Randomization (Day 1) Visit 3 ( 7 ± 3 days after Visit 2, Day 8) Visit 4 (14 ± 3 days after Visit 2, Day 15) Visit 5 (21 ± 3 days after Visit 2, Day 22) Visit 6 (28 ± 3 day after Visit 2, Day 29) A follow-up telephone contact will be made 3 to 5 days after Visit 6 or the Early Withdrawal Visit to assess for any post-treatment adverse events. Subjects who meet the entrance criteria (see Section 5.2.1 Inclusion Criteria and Section 5.2.3 Exclusion Criteria of the protocol) at Visit 1 will enter a 7-day minimum to 14-day maximum “screening” period. The purpose of the screening period is to determine the severity of subjects’ PAR symptoms. During the screening period subjects will be required to rate their nasal and ocular symptoms of allergic rhinitis and record them on an electronic diary (e-diary). Subjects will also complete PNIF measurements and record results on the e-diary. Any medical problems (other than allergic rhinitis) and medications used will also be documented by the subjects. After entering the screening period for a minimum of 7 days, symptomatic subjects who meet the randomization criteria (see Section 5.2.2 Randomization Criteria of the protocol) may be randomly assigned to one of the following once-daily, double-blind treatments: •

FFNS 110mcg

•

Vehicle placebo nasal spray

Subjects who do not meet the entry criteria after 14 days are not eligible for re-screening. All randomized subjects will receive a blinded nasal spray device. Subjects will be instructed to administer 2 sprays from the device into each nostril once daily every morning. Administration of the dose should be performed by alternately spraying one spray in each nostril followed by a second spray in each nostril. The first dose of study drug will be administered before noon during Visit 2 in the clinic. Throughout the treatment period subjects will continue to rate their nasal and ocular symptoms of allergic rhinitis, complete PNIF measurements, and record them on the treatment e-diary. Subjects will also document their study medication administration/compliance on the e8

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diary by answering the question “Did you spray 2 sprays of your medication in each nostril?” Any medical problems (other than allergic rhinitis) and concomitant medications used will also be documented by the subjects, This information is used for sites to query the subject regarding adverse events and concomitant medication use. Subjects will be instructed not to take any anti-allergy/anti-rhinitis medication during the screening or treatment study periods. No allergy rescue medication will be allowed throughout the entire study period. A follow-up phone call to assess for adverse effects will be made by the investigator or designee to the subject within 3 to 5 days after the final clinic visit. If the subject withdraws from the study prior to Visit 6 (Week 4), an Early Withdrawal visit must be completed as soon as possible.

4.

PLANNED ANALYSES

All planned analyses will be performed after sign-off of this RAP. Once the RAP is signed off, programming and validation may commence. Once the database is released and frozen, the study may be unblinded and data displays may be released. If it is found necessary to amend the RAP, all amendments must be completed prior to unblinding the study.

4.1.

Interim Analyses

No interim analyses are planned for this study.

5.

SAMPLE SIZE CONSIDERATIONS

The study randomization is planned for equal allocation of subjects among the two treatment groups. A total of 288 subjects are required for this study, with 144 subjects in each of the two treatment groups: FFNS 110mcg and vehicle placebo. The randomization will be stratified by country (USA, Canada, Germany, Hungary, Estonia, Slovakia, and Russia) to account for possible country effects on the study outcome due to country-specific medical practices. The proposed sample size should provide 90% power to detect a difference of 1.0 between active treatment and placebo in mean change from baseline over the entire treatment period in daily rTNSS, assuming a standard deviation of 2.6 based on data from the previous GSK allergy rhinitis studies. This calculation is based on a two-sample ttest with a 0.05 two-sided significance level.

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ANALYSIS POPULATIONS

The population used in each summary and/or analysis will be noted in the upper left corner of each data display, as per International Data Standards Library (IDSL) standards. The primary population will be the Intent-to-Treat (ITT) Population. The ITT Population is defined as all subjects who are randomized and receive at least one dose of study drug. Unless otherwise specified, analyses based on the ITT Population will include all available data for these subjects. This population will be the basis for all summaries, analyses, listings, and figures of demographic, efficacy, safety, and health outcomes data. The All Subjects Screened Population is defined as all subjects who are screened for inclusion in the study. Subject disposition will be summarized for this population. The Screen Failure Population is defined as all subjects screened for inclusion in the study who are discontinued from the study prior to randomization, or subjects who are misrandomized and receive no administration of study drug. The reasons for withdrawal prior to randomization, and serious adverse events during the screening period will be listed for this population.

7.

TREATMENT COMPARISONS

The primary comparison will be made on the primary efficacy measure between FFNS 110mcg and vehicle placebo.

7.1.

Data Display Treatment and Other Sub-group Descriptors

Treatment groups will be labelled as follows: •

FF 110mcg for the FFNS 110mcg group

•

Placebo for the vehicle placebo nasal spray group.

8.

GENERAL CONSIDERATIONS FOR DATA ANALYSES

All programming will be performed using SAS version 8, or a later release, in a UNIX environment. All output files for tables and listings will be ASCII files in landscape format with 10-point font size. All output for graphs will be provided in postscript (ps) files. Data displays will use International Data Standard Library standards where appropriate. Two-sided statistical tests will be used throughout the analyses. Where confidence intervals are specified, 95% confidence intervals will be calculated. In general, discrete variables will be summarized using frequency distributions, and continuous variables will be summarized using the number of observations, mean, standard deviation or standard error, median, minimum, and maximum.

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Any deviation(s) from the analysis plan as outlined in the protocol will be documented both in this RAP and in the CSR. Any deviations from the RAP will be documented in the CSR.

8.1.

Multicentre Studies

This study will be conducted in USA, Canada, Germany, Hungary, Estonia, Slovakia, and Russia. The study randomization will be stratified by country and will be centrally randomized within each country. With approximately 40-50 investigative sites expected to participate in the study, most of the investigational sites will have a small number of subjects, expected to be 5-10 per site. In the initial model fitting for the primary efficacy endpoint, a treatment-by-country interaction term will be included in order to explore the uniformity of treatment effect across the countries. If a significant interaction is found (p-value ≤ 0.10), an investigation will be undertaken and reported in the Statistical Methods Appendix of the CSR. If the inference for treatment in the main effects model is similar to the model that also includes the interaction term, the investigation is complete, otherwise further investigation is warranted and will be included in the Statistical Methods Appendix. The treatment-by-country interaction term will not be included in the analysis model for reporting.

8.2.

Other Strata and Covariates

In addition to country, baseline value, age, and gender will be included as covariates in all efficacy analyses when appropriate.

8.3.

Examination of Subgroups

For the primary efficacy endpoint (mean change from baseline over the entire treatment period in daily rTNSS), subgroup summary tables will be provided by age group (12 to <18, 18 to <65, and ≥65 years of age), and by country (if country has a significant effect on the primary efficacy endpoint). For the all adverse events during the treatment period, subgroup summary tables will be provided by age group (12 to <18, 18 to <65, and ≥65 years of age) and gender.

8.4.

Multiple Comparisons and Multiplicity

All results from the analyses of the primary efficacy, secondary efficacy, and health outcomes endpoints will be reported.

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The primary efficacy endpoint will serve as a gatekeeper for the interpretation of treatment comparisons for the key secondary efficacy and health outcomes endpoints. If H0 is rejected at the 0.05 level, the conclusion will be there is a difference between FFNS 110mcg and vehicle placebo, and the p-values for the key secondary efficacy and health outcomes endpoints may be interpreted according to the rules for multiplicity adjustment described below. If H0 is not rejected, the conclusion will be there is no difference between FFNS 110mcg and vehicle placebo, and all other p-values will be used for descriptive and exploratory purposes only. To control for multiplicity across the key secondary efficacy endpoints and the health outcomes endpoint (mean change from baseline to endpoint in the global score of the RQLQ(S)) tests of H0 will be performed in a sequential manner to control the Type I error rate at 0.05 as follows: 1.

Mean change from baseline over the entire treatment period in AM, pre-dose iTNSS.

2.

Mean change from baseline over the entire treatment period in daily rTOSS.

3.

Mean change from baseline to endpoint in the global score of the RQLQ(S).

No multiplicity adjustments will be made on the other secondary efficacy endpoints. Any p-values ≤ 0.05 will be identified as nominally significant.

9.

DATA HANDLING CONVENTIONS

9.1.

Premature Withdrawal and Missing Data

For any subject who withdraws from the study early, all available data up to the time of discontinuation of study drug will be included in the analyses for the ITT Population. The values for the total nasal symptom score (TNSS) range from 0 to 12, since each of the 4 individual symptoms are scored on a 4-point scale of 0 to 3, and the TNSS is defined as the sum of the 4 individual nasal symptom scores. If for a given subject at a given assessment time (i.e., AM or PM) any of the 4 individual symptom scores are missing, then the TNSS will be considered missing for that assessment time. If one, but not both, of the AM and PM TNSS is missing for a given day (i.e., a dosing interval during the treatment period), the non-missing TNSS for that day will used as the daily TNSS for that day. Missing total ocular symptom score (TOSS) data (based on the 3 individual ocular symptom scores) will be handled in the same manner as for the TNSS.

9.2.

Derived and Transformed Data

9.2.1.

Calculation of Days on Treatment

When calculating the number of days relative to the date of randomization (i.e., treatment start date), the date of randomization will be counted as Day 1. Days on treatment will be calculated as follows: 12

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Days on Treatment = (date of the event – date of randomization) + 1 9.2.2.

Calculation of Baseline, Treatment Period, and Weekly Means for Symptom Scores

For all diary-based efficacy assessments, the date of randomization (i.e., treatment start date) will be used as the reference date in defining the baseline and treatment periods. For purposes of efficacy analyses based on diary data, data collected prior to the baseline period or after Day 29 (the end of the 4-week treatment period) will be excluded, as will data collected after a subject discontinued study drug. The baseline period is defined as the 4 days prior to randomization, including the AM symptom assessment on the day of randomization (i.e., day of treatment initiation). For AM assessments, the baseline period includes the date of randomization and the 3 consecutive days prior to randomization. For PM assessments, the baseline period includes the 4 consecutive days prior to randomization. Baseline values for symptom scores are defined as the mean of the non-missing values for each symptom score during the baseline period. The treatment period is defined as the first 28 consecutive days after randomization. For the AM symptom assessments, the treatment period includes the first 28 consecutive days after the date of randomization. For the PM assessments, the treatment period includes the date of randomization and the 27 consecutive days following randomization. Treatment period values for symptom scores are defined as the mean of the non-missing values for each symptom score during the treatment period. Weekly values for symptom scores are defined in the same manner as the treatment period values (i.e., the mean of the non-missing values for each symptom score during a given 7-day week). 9.2.3.

Calculation of Total Nasal Symptom Scores and Total Ocular Symptom Scores

The TNSS for each assessment time point is defined as the sum of the 4 individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing, and will range from 0 to 12. The TOSS for each assessment time point is defined as the sum of the 3 individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness, and will range from 0 to 9. Each of the 4 individual nasal symptoms and the 3 individual ocular symptoms is evaluated by the subject using a 4-point (0 to 3) categorical scale and recorded on the e-diary. The reflective scores (i.e., rTNSS and rTOSS) are ratings of the severity of symptoms over the previous 12 hours and are performed in the AM and PM. Daily (i.e., during one dosing interval) reflective scores are defined as the average of the PM reflective scores and the AM reflective scores of the next day prior to the AM dosing. For example, the Day 1 rTNSS will be computed as [(PM rTNSS) Day 1, first day of dosing + (AM rTNSS) Day 2, prior to 2nd dosing] / 2, and the Day 28 rTNSS will be computed as [(PM rTNSS) Day 28, last day of dosing + (AM rTNSS) Day 29, last clinic visit] / 2. 13

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Calculation of Change from Baseline and Percent Change from Baseline

Change from baseline will be calculated for all analyses as the on-treatment value minus the baseline value. Percent change from baseline will be calculated for each subject, where specified, as follows: % Change from Baseline = change from baseline x 100 baseline 9.2.5.

Calculation of Treatment Compliance

The number of doses of study drug taken during the double-blind 4-week treatment period will be estimated based on information recorded by the subject on the e-diary. Subjects will document their study medication administration/compliance on the e-diary by answering the question “Did you spray 2 sprays of your medication in each nostril?” Each occurrence of “yes” in response to this question will count as one dose of study medication. Percent treatment compliance will be calculated for each subject as follows: % Treatment Compliance =

x 100, where # of doses used expected # of doses used

•

# of doses used = sum of the “yes” responses to the question “Did you spray 2 sprays of your medication in each nostril?” for all days on treatment

•

expected # of doses used = # of days on treatment.

9.2.6.

Determination of Extent of Exposure to Study Medication

The extent of exposure to study medication will be defined as the number of days on study drug and will be calculated for each subject as follows: Exposure = (treatment stop date – treatment start date) + 1 If the treatment stop date is missing then the subject discontinuation/completion date will be used for treatment stop date. If the study discontinuation/completion date is also missing then the extent of exposure will be set to missing. If treatment start date is missing then the randomization date (i.e. date of Visit 2) of the subject will be used for treatment start date. 9.2.7.

Calculation of Adverse Event Duration and Time to Onset of Adverse Event

The adverse event duration for those adverse events that resolved, will be calculated as follows:

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Adverse Event Duration = (date of resolution - adverse event onset date) + 1 The time to onset of each adverse event occurring during the screening period will be calculated as (adverse event onset date - treatment start date). The time to onset of each adverse event occurring during the treatment period or post-treatment period will be calculated as (adverse event onset date – treatment start date) + 1. 9.2.8.

Scoring of the Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities

The Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities [RQLQ(S)] is a 28-item, self-administered, disease-specific (allergic rhinitis) instrument, which assesses quality of life over a one-week interval.1 In the standardized version of the RQLQ, the RQLQ(S), the 3 “patient-specific” activity questions have been replaced by generic activities. The RQLQ(S) will be administered at Visit 2 (Randomization, Day 1) and Visit 6 (Week 4)/Early Withdrawal and scored according to the instrument developers’ guidelines. The RQLQ consists of 28 items scored on a 7-point (0 to 6) categorical scale, with higher scores indicating more impairment on quality of life. These 28 items constitute 7 domains as follows: •

Activities (3 items): 1, 2, 3

•

Sleep (3 items): 4, 5, 6

•

Non-Hayfever Symptoms (7 items): 7, 8, 9, 10, 11, 12, 13

•

Practical Problems (3 items): 14, 15, 16

•

Nasal Symptoms (4 items): 17, 18, 19, 20

•

Eye Symptoms (4 items): 21, 22, 23, 24

•

Emotional (4 items): 25, 26, 27, 28

At any time point mean scores for each individual domain will be calculated for each subject by averaging the item scores included within that domain. The global score at any time point will be calculated for each subject by averaging all item scores. Each individual domain mean score for any subject at any time point will only be calculated if at least 75% of the items in that domain are answered. The global score for any subject at any time point will only be calculated if at least 75% of all items are answered. Otherwise, mean scores will be set to missing.

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Assessment Windows

Assessment windows for the scheduled study visits are as follows: Visit 1 Screening (7 to 14 days prior to Randomization) Visit 2 Randomization (Day 1) Visit 3 ( 7 ± 2 days after Visit 2, Day 8) Visit 4 (14 ± 2 days after Visit 2, Day 15) Visit 5 (21 ± 2 days after Visit 2, Day 22) Visit 6 (28 ± 1 day after Visit 2, Day 29). Individual assessments collected outside of the assessment window for scheduled visits will be included in the ITT analysis without adjustment. If multiple assessments are collected within the same assessment window, the last valid value prior to randomization will be used as the baseline value and the first valid value will be used for postrandomization visits.

10.

STUDY POPULATION

With the exception of the disposition of subjects screened and the reasons for withdrawal prior to randomization, all summaries of study population data will be provided for the ITT Population.

10.1.

Disposition of Subjects

The disposition of subjects screened for this study, including screening failure by major reason per the CRF and double-blind randomization, will be summarized for the All Subjects Screened Population. A listing of screened subjects who are excluded from the ITT Population and the reason(s) for exclusion will be provided for the Screen Failure Population. The number of subjects enrolled at each investigational site will be summarized by treatment group. A cross-reference of investigator, sorted by subject will also be produced. The disposition of subjects at the end of the study, including early withdrawal from the study by major reason per the CRF will be summarized by treatment group. A listing of subjects withdrawn early from the study and the withdrawal reasons will also be provided. The number of subjects attending each study visit will be summarized by treatment group.

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Protocol Deviations

Any inclusion/exclusion/randomization criteria not met at Visit 1 (Screening) or Visit 2 (Randomization) will be summarized by treatment group. Other deviations will be noted as applicable, including use of prohibited concomitant medications during the study (i.e., screening and treatment periods), incorrect study drug dispensing, and any other deviations deemed to have the potential for notably influencing the study results. A listing of subjects with protocol deviations will be provided. Visits that are outside of protocol-specified assessment windows will also be summarized by treatment group. Subjects for whom the treatment blind was broken will be listed.

10.3.

Demographic and Baseline Characteristics

Demographic characteristics, including race and racial combinations, will be summarized by treatment group and listed by subject. Age will be calculated based on the date of randomization for the ITT Population, and based on the date of Visit 1 (Screening) for the Screen Failure Population. Allergy history will be summarized by treatment group and listed by subject. Baseline nasal and ocular symptom scores (see Section 9.2.2) will also be summarized by treatment group. This will include both reflective and instantaneous assessments. Medical conditions will be summarized by treatment group.

10.4.

Concomitant Medications

The CRF texts for concomitant medications will be coded using the GSKDrug dictionary, and will be reported using Anatomical-Therapeutical-Chemical (ATC) Level 1 and ingredients. Ingredients will be summarized within ATC Level 1. The relationship of ATC Level 1, ingredients, and verbatim text will be listed. Concomitant medications, categorized by drug class (ATC Level I), will be summarized during the screening period and the treatment period by treatment group. Concomitant medications during the screening period will be defined as any medications used for any length of time during the screening period (i.e. Visit 1 to one day prior to Visit 2). Concomitant medications during the treatment period will be defined as any medications used for any length of time during the treatment period (i.e. Visit 2 to the treatment stop date). Concomitant medications during the study period will also be listed by subject.

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Treatment Compliance

Subject-reported compliance with the dosing regimen will be summarized by treatment group as a percentage for the double-blind treatment period. Treatment compliance percentages will be calculated for each subject based on the information recorded by the subject on the e-diary (see Section 9.2.5).

11.

EFFICACY ANALYSES

Efficacy measures have been noted in Section.2.2.1 All efficacy measures for nasal (rhinorrhea, nasal congestion, nasal itching, and sneezing) and ocular (itching/burning eyes, tearing/watering eyes, and eye redness) symptoms are based on subject-rated, individual symptom assessments as evaluated on a 4-point (0 to 3) categorical scale, recorded on the e-diary. The rating for assessing the severity of nasal and ocular symptoms is defined for each individual symptom as follows: 0=none (symptom is not present) 1=mild (sign/symptom is clearly present but minimal awareness; easily tolerated) 2=moderate (definite awareness of sign/symptom that is bothersome but tolerable) 3=severe (sign/symptom is hard to tolerate; causes interference with activities of daily living and/or sleeping) The reflective rating represents how the subject has been feeling over the preceding 12 hours. This assessment provides information on how effective the treatment is throughout a 12-hour period of time and will be performed twice daily (AM and PM). The AM assessment is performed in the morning prior to administering the dose of study drug and assesses how the subject felt during the night. The PM assessment is performed approximately 12 hours after dosing and before bedtime and assesses how the subject felt during the day. The instantaneous rating represents how the subject is feeling at the time of the assessment, or at that “instant”. The instantaneous assessment will be performed once daily, in the morning prior to administering the dose of study drug. This assessment will provide information on the efficacy of the treatment at the end of the 24-hour dosing interval. In each summary table, sample size, raw mean, standard error of the mean, median, minimum, and maximum will be given. In each analysis table, sample size, least square mean, standard error of the least square mean, least square mean difference, p-value and 95% confidence interval (where appropriate) will be given for all treatment comparisons (unadjusted for multiple comparisons).

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11.1.

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Primary Efficacy Analysis(es)

The primary efficacy endpoint is the mean change from baseline over the entire treatment period in daily rTNSS as evaluated on a 4-point categorical scale (see Section 9.2.3). The primary analysis method will be the comparison of treatment groups (FFNS 110mcg vs. placebo) using analysis of covariance (ANCOVA), adjusting for baseline daily rTNSS, country, age, and gender. Mean daily rTNSS will be illustrated over the 4-day baseline period and the 28-day treatment period by treatment group. Summary statistics will be displayed for baseline, Week 1, Week 2, Week 3, Week 4, and the entire treatment period (see Section 9.2.2). Mean change from baseline in daily rTNSS will be illustrated over the 28-day treatment period by treatment group. Change from baseline in daily rTNSS over the entire treatment period will be summarized and the mean change will be analyzed. The least square mean changes from baseline will be summarized and FFNS 110mcg will be compared to placebo. The 95% confidence interval for the mean difference between FFNS 110mcg and placebo will also be reported, as well as the p-value corresponding to the test of significance for the mean difference. The change from baseline in daily rTNSS over Week 1, Week 2, Week 3, and Week 4 will also be summarized and analyzed. The analysis results of changes over Week 1, Week 2, Week 3, and Week 4 will be used to reinforce the robustness of the primary efficacy endpoint and will not be adjusted for multiplicity. Summary statistics will be provided for the primary efficacy measure by age group (i.e., 12 to < 18 years, 18 to <64 years, and ≥65 years). If country has a significant effect on the primary efficacy endpoint, summary statistics for the primary efficacy measure will also be provided by country.

11.2.

Secondary Efficacy Analysis(es)

The secondary efficacy measures of nasal symptoms and ocular symptoms will be analyzed in a similar manner to the primary efficacy analysis. The analysis method will be the comparison of FFNS 110mcg versus placebo using ANCOVA adjusting for baseline value, country, age, and gender. With the exception of the key secondary efficacy endpoints (see Section 2.2.1.2), the secondary efficacy analyses results will be used to support the results for the primary and the key secondary efficacy endpoints and will not be adjusted for multiplicity (see Section 8.4).

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11.2.1.

Key Secondary Efficacy Analyses

11.2.1.1.

Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score

Mean AM pre-dose iTNSS (see Section 9.2.3) will be illustrated over the 4-day baseline period and the 28-day treatment period by treatment group. Summary statistics will be displayed for baseline, Week 1, Week 2, Week 3, Week 4, and over the entire treatment period. Mean change from baseline in AM pre-dose iTNSS will be illustrated over the 28-day treatment period by treatment group. Change from baseline in AM pre-dose iTNSS over Week 1, Week 2, Week 3, Week 4, and the entire treatment period will be summarized and the mean change will be analyzed. 11.2.1.2.

Mean Change from Baseline in daily reflective Total Ocular Symptom Score

Mean daily rTOSS (see Section 9.2.3) will be illustrated over the 4-day baseline period and the 28-day treatment period by treatment group. Summary statistics will be displayed for baseline, Week 1, Week 2, Week 3, Week 4, and over the entire treatment period. Mean change from baseline in daily rTOSS will be illustrated over the 28-day treatment period by treatment group. Change from baseline in daily rTOSS over Week 1, Week 2, Week 3, Week 4, and the entire treatment period will be summarized and the mean change will be analyzed. 11.2.2.

Other Secondary Efficacy Analyses

11.2.2.1.

Total Nasal Symptoms

The following measures (see Section 9.2.3) will be illustrated over the 4-day baseline period and 28-day treatment period by treatment group, and summary statistics will be displayed for baseline, Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Mean AM rTNSS

•

Mean PM rTNSS

The following measures will be summarized for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Change from baseline in AM rTNSS

•

Change from baseline in PM rTNSS

•

Percent change from baseline in daily rTNSS

•

Percent change from baseline in AM pre-dose iTNSS 20

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The following measures will be illustrated over the 28-day treatment period, and analyzed for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Mean change from baseline in AM rTNSS

•

Mean change from baseline in PM rTNSS

•

Mean percent change from baseline in daily rTNSS

•

Mean percent change from baseline in AM pre-dose iTNSS

11.2.2.2.

Individual Nasal Symptoms

The following measures will be summarized for baseline, Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Daily reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

AM pre-dose instantaneous individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

AM reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

PM reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

The following measures will be summarized for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Change from baseline in daily reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Change from baseline in AM pre-dose instantaneous individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Change from baseline in AM reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Change from baseline in PM reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

The following measures will be analyzed for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Mean change from baseline in daily reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline in AM pre-dose instantaneous individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline in AM reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

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•

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Mean change from baseline in PM reflective individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing Total Ocular Symptoms

The following measures (see Section 9.2.3) will be illustrated over the 4-day baseline period and 28-day treatment period by treatment group, and summary statistics will be displayed for baseline, Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Mean AM pre-dose iTOSS

•

Mean AM rTOSS

•

Mean PM rTOSS

The following measures will be summarized for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Change from baseline in AM pre-dose iTOSS

•

Change from baseline in AM rTOSS

•

Change from baseline in PM rTOSS

The following measures will be illustrated over the 28-day treatment period, and analysed for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Mean change from baseline in AM pre-dose iTOSS

•

Mean change from baseline in AM rTOSS

•

Mean change from baseline in PM rTOSS

11.2.2.4.

Individual Ocular Symptoms

The following measures will be summarized for baseline, Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Daily reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

AM pre-dose instantaneous individual nasal symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

AM reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

PM reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

The following measures will be summarized for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Change from baseline in daily reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness 22

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•

Change from baseline in AM pre-dose instantaneous individual nasal symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

Change from baseline in AM reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

Change from baseline in PM reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

The following measures will be analyzed for Week 1, Week 2, Week 3, Week 4, and the entire treatment period: •

Mean change from baseline in daily reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

Mean change from baseline in AM pre-dose instantaneous individual nasal symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

Mean change from baseline in AM reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

•

Mean change from baseline in PM reflective individual ocular symptom scores for itching/burning eyes, tearing/watering eyes, and eye redness

11.2.2.5.

Time to Onset of Treatment Effect

Onset of treatment effect will be assessed by the mean change from baseline in AM predose iTNSS and the mean change from baseline in daily rTNSS (Day 1 to Day 28), and supported by the mean change from baseline in AM rTNSS and PM rTNSS. Daily rTNSS and change from baseline in daily rTNSS will be summarized by treatment group for Day 1 to Day 28. Mean change from baseline in daily rTNSS will be analyzed for Day 1 to Day 28. AM rTNSS and change from baseline in AM rTNSS will be summarized by treatment group for Day 1 to Day 28. Mean change from baseline in AM rTNSS will be analyzed for Day 1 to Day 28. PM rTNSS and change from baseline in PM rTNSS will be summarized by treatment group for Day 1 to Day 28. Mean change from baseline in PM rTNSS will be analyzed for Day 1 to Day 28. 11.2.2.6.

Time to Maximum Effect

Time to maximum treatment effect will be evaluated by the mean change from baseline in daily rTNSS over Day 1 to Day 28 of the treatment period. Mean daily rTNSS will be summarized by treatment group for Day 1 to Day 28. Mean change from baseline in daily rTNSS will be summarized and analyzed for Day 1 to Day 28.

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SAFETY ANALYSES

Safety endpoints have been noted in Section 2.2.2. Safety data will be summarized and/or listed by treatment group. All summaries of safety data will be provided for the ITT Population. Serious adverse events will also be listed for the Screen Failure Population.

12.1.

Extent of Exposure

The number and percentage of subjects with extent of exposure to study medication (see Section 9.2.6) within the following timeframes will be displayed: 1 to 7 days, 8 to 14 days, 15 to 21 days, 22 to 27 days, 28 to 30 days, and 30+ days. Summary statistics will also be displayed.

12.2.

Adverse Events

The CRF texts for adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and will be reported using the primary System Organ Class (SOC) and Preferred Term. Adverse events will be summarized and grouped by primary SOC and by adverse event (i.e., Preferred Term) within primary SOC. Results will be displayed in the order of decreasing frequency, both across primary SOC and within primary SOC. The number of subjects with one or more events of any type will also be calculated. The relationship of primary SOC, Preferred Terms, and verbatim text will be listed. The following summaries and listings of adverse events will be provided: •

summary of all adverse events during the screening period

•

summary of all adverse events during the treatment period

•

summary of adverse events with an incidence rate >3% in the FFNS 110mcg group and more common than in the placebo group during the treatment period

•

summary of adverse events with an incidence rate of 1% to 3% in the FFNS 110mcg group and more common than those in the placebo group during the treatment period

•

summary of all adverse events during the post-treatment period

•

listing of all adverse events during the study period

•

summary of drug-related adverse events (events the investigator determined to have a reasonable possibility of being caused by the study drug) during the study period

•

listing of drug-related adverse events during the study period

•

summary of all adverse events during the treatment period by age group (i.e., 12 to <18 years of age, 18 to <65 years of age, and ≥65 years of age)

•

summary of all adverse events during the treatment period by gender (i.e., female and male).

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Adverse events during the screening period will be defined as events with an onset date the same as or after the screening date (Visit 1) but prior to the treatment start date. Adverse events during the treatment period will be defined as events with an onset date the same as or after the treatment start date but prior to or the same as the treatment stop date + 1. Adverse events during the post-treatment period will be defined as events with an onset date after the treatment stop date + 1. Demographic details (e.g., age, gender, race, and ethnicity), as well as details of the individual adverse events (see Section 9.2.7), will be included on the listings. The listings will be sorted within subject by the adverse event date of onset.

12.3.

Deaths and Serious Adverse Events

Deaths and non-fatal serious adverse events will be summarized and listed in the same manner described above for all adverse events as follows: •

listing of serious adverse events during the screening period for the Screen Failure Population

•

listing of serious adverse events during the study period for the ITT Population.

Any deaths and non-fatal serious adverse events reported during this study will be summarized in case narratives written by GSK Global Clinical Safety and Pharmacovigilance personnel.

12.4.

Pregnancies (as applicable)

Pregnancies reported during this study will be summarized in case narratives written by GSK Global Clinical Safety and Pharmacovigilance personnel.

12.5.

Clinical Laboratory Evaluations

For each laboratory analyte, the normal range determined by the central laboratory will be displayed. Laboratory data (haematology, chemistry, and electrolytes) will be collected during Visit 1 (Screening) and Visit 6 (Week 4) / Early Withdrawal. The number and percentage of subjects with laboratory values outside the normal range will be summarized by study visit for each laboratory analyte. Shift tables will summarize post-treatment flag values [low (L), normal (N), or high (H)] for each analyte, relative to their baseline flag values. Laboratory values are flagged as "low" if they are less than the lower limit of the normal range, "normal" if they are within the normal range, and "high" if they are above the upper limit of the normal range.

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Baseline is defined as the last laboratory values captured prior to randomization [i.e., at Visit 1 or, where applicable, a repeat assessment performed prior to administration of the first dose of study medication at Visit 2 (Randomization, Day 1)]. The endpoint is defined as the first post-treatment value (i.e. laboratory value collected at Visit 6 or withdrawal visit). Shift from baseline to endpoint (Week 4 / discontinuation) in laboratory value is categorized, for each laboratory analyte, as follows: To High To Normal or No Change To Low

L to H, N to H L to N, H to N L to L, N to N, H to H N to L, H to L

The number of subjects in each category will be summarized for each laboratory analyte. All laboratory values for subjects with at least one post-treatment laboratory value (including repeat assessments) outside the normal range will be listed.

12.6.

Other Safety Measures

12.6.1.

Nasal Examination

The following nasal examinations will be performed at each study visit: •

Mucosal bleeding (absent or present)

•

Ulcers (absent or present; location and severity when present)

•

Polyposis (absent or present; location and severity when present)

The nasal examination results will be summarized by study visit for each of the 6 parameters listed above as follows: mucosal bleeding (absent if absent in both nostrils, present otherwise), ulcers (absent if absent in both nostrils, present otherwise), and polyposis (absent if absent in both nostrils, present otherwise). Shifts from baseline [defined as examination results from Visit 2 (Randomization)] to endpoint [defined as examination results from Visit 6 (Week 4) or Early Withdrawal visit] will also be summarized for each nasal examination parameter. For each of the nasal examination parameters, a change from present at baseline to absent at endpoint will be considered improvement; likewise a change from absent at baseline to present at endpoint will be considered worsening. Subjects with at least one occurrence of worsening ulcers at any time post-baseline will be listed, as will subjects with at least one occurrence of worsening mucosal bleeding at any time post-baseline. Worsening ulcers is defined as absent at baseline and present post-baseline OR present/small at baseline and present/large post-baseline. Worsening mucosal bleeding is defined as absent at baseline and present post-baseline. All nasal examination results will be listed for those subjects with at least one abnormal nasal examination result for any parameter post-baseline. 26

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A listing of subjects with clinical evidence of nasal candidiasis will be provided. 12.6.2.

Vital Signs

Vital signs will be collected during Visit 1 (Screening) and Visit 6 (Week 4)/Early Withdrawal. Summary statistics for systolic blood pressure (mmHg), diastolic blood pressure (mmHg), and heart rate (beats/min) will be provided by visit.

13.

HEALTH OUTCOMES ANALYSES

Health outcomes measures have been noted in Section 2.2.3 Health Outcomes Endpoints.

13.1.

Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities

The RQLQ will be administered during Visit 2 (Randomization, Day1) and Visit 6 (Week 4)/Early Withdrawal and scored according to the instrument developers’ guidelines (see Section 9.2.8 Scoring of the Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities The primary analysis of the RQLQ(S) is the pairwise treatment comparison of FFNS 110mcg and placebo in the mean change from baseline to endpoint for the global score. Baseline is defined as the global score from Visit 2. Endpoint is defined as the global score from the last available questionnaire completed at least one week after the baseline questionnaire. An ANCOVA model including terms for treatment, country, treatmentby-country interaction, and baseline will be used. A mean change from baseline of 0.5 for the RQLQ scores will be considered the smallest change that subjects perceive as beneficial.2 If the difference between treatment groups in the global score is found to be statistically significant, then the individual domain scores will be compared between treatment groups.

14.

PHARMACOGENETIC DATA ANALYSES

Genotyping data will be the subject of a separate reporting and analysis plan.

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REFERENCES

1. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire. J Allergy Clin Immunol 1999;104:364-9. 2. Juniper EF, et al. Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol 1994;47(1):81-87.

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16.

ATTACHMENTS

16.1.

Table of Contents for Data Display Specifications

Figures Efficacy

7.1

Mean Daily Reflective Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.2

Mean Change from Baseline in Daily Reflective Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.3

Mean AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.4

Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.5

Mean Daily Reflective Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.6

Mean Change from Baseline in Daily Reflective Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.7

Mean AM Reflective Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.8

Mean Change from Baseline in AM Reflective Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.9

Mean PM Reflective Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.10

Mean Change from Baseline in PM Reflective Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.11

Mean Percent Change from Baseline in Daily Reflective Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.12

Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Score over the Treatment Period (Population: ITT)

7.13

Mean AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period (Population: ITT)

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7.14

Mean Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.15

Mean AM Reflective Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.16

Mean Change from Baseline in AM Reflective Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.17

Mean PM Reflective Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.18

Mean Change from Baseline in PM Reflective Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.19

Mean Percent Change from Baseline in Daily Reflective Total Ocular Symptom Score over the Treatment Period (Population: ITT)

7.20

Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Score over the Treatment Period (Population: ITT)

Tables Study Population

6.1

Summary of Screening Subject Disposition (Population: All Subjects Screened)

6.2

Listing of Reasons for Screening Failure (Population: Screen Failure)

6.3

Summary of Subject Enrollment by Investigator (Population: ITT)

6.4

Reference Listing of Subject Number to Investigator Number (Population: ITT)

6.5

Summary of Subject Accountability: End of Study Record (Population: ITT)

6.6

Listing of Subject Withdrawals: End of Study Record (Population: ITT)

6.7

Summary of Number of Subjects at Each Visit (Population:ITT)

6.8

Summary of Inclusion/Exclusion/Randomization Criteria Deviations (Population: ITT)

6.9

Listing of Subjects with Inclusion/Exclusion/Randomization Criteria Deviations (Population: ITT)

6.10

Summary of Protocol Deviations (Population: ITT)

6.11

Listing of Protocol Deviations (Population: ITT)

6.12

Summary of Visit Spacing Relative to Protocol Specifications (Population:ITT) 30

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6.13

Listing of Subjects for Whom the Treatment Blind was Broken During the Study (Population: ITT)

6.14

Summary of Demographic Characteristics (Population: ITT)

6.15

Summary of Race and Racial Combinations (Population: ITT)

6.16

Summary of Race and Racial Combination Details (Population: ITT)

6.17

Listing of Subject Demographic and Baseline Characteristics (Population: ITT)

6.18

Listing of Race (Population: ITT)

6.19

Summary of Allergy History (Population: ITT)

6.20

Listing of Allergy History (Population: ITT)

6.21

Summary of Baseline Nasal Symptom Scores (Population: ITT)

6.22

Summary of Baseline Ocular Symptom Scores (Population: ITT)

6.23

Summary of Current Medical Conditions (Population: ITT)

6.24

Relationship of ATC Level, Ingredients, and Verbatim Text

6.25

Summary of Concomitant Medications During the Screening Period (Population: ITT)

6.26

Summary of Concomitant Medications During the Treatment Period (Population: ITT)

6.27

Listing of Concomitant Medications During the Study Period (Population: ITT)

6.28

Summary of Treatment Compliance (Population: ITT)

6.29

Listing of Subjects with Nasal Spray Device Malfunction (Population: ITT)

Efficacy

7.1

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT)

7.2

Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores (Population: ITT)

7.3

Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Population: ITT)

7.4

Analysis of Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Population: ITT)

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7.5

Summary of Daily Reflective Total Ocular Symptom Scores (Population: ITT)

7.6

Analysis of Mean Change from Baseline in Daily Reflective Total Ocular Symptom Scores (Population: ITT)

7.7

Summary of AM Reflective Total Nasal Symptom Scores (Population: ITT)

7.8

Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores (Population: ITT)

7.9

Summary of PM Reflective Total Nasal Symptom Scores (Population: ITT)

7.10

Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores (Population: ITT)

7.11

Summary of Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores (Population: ITT)

7.12

Analysis of Mean Percent Change from Baseline in Daily Reflective Total Nasal Symptom Scores (Population: ITT)

7.13

Summary of Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Population: ITT)

7.14

Analysis of Mean Percent Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores (Population: ITT)

7.15

Summary of Daily Reflective Symptom Scores for Rhinorrhea (Population: ITT)

7.16

Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Rhinorrhea (Population: ITT)

7.17

Summary of Daily Reflective Symptom Scores for Nasal Congestion (Population: ITT)

7.18

Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Congestion (Population: ITT)

7.19

Summary of Daily Reflective Symptom Scores for Nasal Itching (Population: ITT)

7.20

Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Nasal Itching (Population: ITT)

7.21

Summary of Daily Reflective Symptom Scores for Sneezing (Population: ITT)

7.22

Analysis of Mean Change from Baseline in Daily Reflective Symptom Scores for Sneezing (Population: ITT)

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7.23

Summary of AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea (Population: ITT)

7.24

Analysis of Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Rhinorrhea (Population: ITT)

7.25

Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion (Population: ITT)

7.26

Analysis of Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Congestion (Population: ITT)

7.27

Summary of AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching (Population: ITT)

7.28

Analysis of Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Nasal Itching (Population: ITT)

7.29

Summary of AM Pre-Dose Instantaneous Symptom Scores for Sneezing (Population: ITT)

7.30

Analysis of Change from Baseline in AM Pre-Dose Instantaneous Symptom Scores for Sneezing (Population: ITT)

7.31

Summary of AM Reflective Symptom Scores for Rhinorrhea (Population: ITT)

7.32

Analysis of Change from Baseline in AM Reflective Symptom Scores for Rhinorrhea (Population: ITT)

7.33

Summary of AM Reflective Symptom Scores for Nasal Congestion (Population: ITT)

7.34

Analysis of Change from Baseline in AM Reflective Symptom Scores for Nasal Congestion (Population: ITT)

7.35

Summary of AM Reflective Symptom Scores for Nasal Itching (Population: ITT)

7.36

Analysis of Change from Baseline in AM Reflective Symptom Scores for Nasal Itching (Population: ITT)

7.37

Summary of AM Reflective Symptom Scores for Sneezing (Population: ITT)

7.38

Analysis of Change from Baseline in AM Reflective Symptom Scores for Sneezing (Population: ITT)

7.39

Summary of PM Reflective Symptom Scores for Rhinorrhea (Population: ITT)

7.40

Analysis of Change from Baseline in PM Reflective Symptom Scores for Rhinorrhea (Population: ITT)

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7.41

Summary of PM Reflective Symptom Scores for Nasal Congestion (Population: ITT)

7.42

Analysis of Change from Baseline in PM Reflective Symptom Scores for Nasal Congestion (Population: ITT)

7.43

Summary of PM Reflective Symptom Scores for Nasal Itching (Population: ITT)

7.44

Analysis of Change from Baseline in PM Reflective Symptom Scores for Nasal Itching (Population: ITT)

7.45

Summary of PM Reflective Symptom Scores for Sneezing (Population: ITT)

7.46

Analysis of Change from Baseline in PM Reflective Symptom Scores for Sneezing (Population: ITT)

7.47

Summary of AM Pre-Dose Instantaneous Total Ocular Symptom Scores (Population: ITT)

7.48

Analysis of Change from Baseline in AM Pre-Dose Instantaneous Total Ocular Symptom Scores (Population: ITT)

7.49

Summary of AM Reflective Total Ocular Symptom Scores (Population: ITT)

7.50

Analysis of Change from Baseline in AM Reflective Total Ocular Symptom Scores (Population: ITT)

7.51

Summary of PM Reflective Total Ocular Symptom Scores (Population: ITT)

7.52

Analysis of Change from Baseline in PM Reflective Total Ocular Symptom Scores (Population: ITT)

7.53

Summary of Daily Reflective Symptom Scores for Eye Itching/Burning (Population: ITT)

7.54

Analysis of Mean Change from Baseline In Daily Reflective Symptom Scores for Eye Itching/Burning (Population: ITT)

7.55

Summary of Daily Reflective Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.56

Analysis of Mean Change from Baseline In Daily Reflective Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.57

Summary of Daily Reflective Symptom Scores for Eye Redness (Population: ITT)

7.58

Analysis of Mean Change from Baseline In Daily Reflective Symptom Scores for Eye Redness (Population: ITT)

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7.59

Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning (Population: ITT)

7.60

Analysis of Mean Change from Baseline In AM Pre-Dose Instantaneous Symptom Scores for Eye Itching/Burning (Population: ITT)

7.61

Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.62

Analysis of Mean Change from Baseline In AM Pre-Dose Instantaneous Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.63

Summary of AM Pre-Dose Instantaneous Symptom Scores for Eye Redness (Population: ITT)

7.64

Analysis of Mean Change from Baseline In AM Pre-Dose Instantaneous Symptom Scores for Eye Redness (Population: ITT)

7.65

Summary of AM Reflective Symptom Scores for Eye Itching/Burning (Population: ITT)

7.66

Analysis of Mean Change from Baseline In AM Reflective Symptom Scores for Eye Itching/Burning (Population: ITT)

7.67

Summary of AM Reflective Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.68

Analysis of Mean Change from Baseline In AM Reflective Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.69

Summary of AM Reflective Symptom Scores for Eye Redness (Population: ITT)

7.70

Analysis of Mean Change from Baseline In AM Reflective Symptom Scores for Eye Redness (Population: ITT)

7.71

Summary of PM Reflective Symptom Scores for Eye Itching/Burning (Population: ITT)

7.72

Analysis of Mean Change from Baseline In PM Reflective Symptom Scores for Eye Itching/Burning (Population: ITT)

7.73

Summary of PM Reflective Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.74

Analysis of Mean Change from Baseline In PM Reflective Symptom Scores for Eye Tearing/Watering (Population: ITT)

7.75

Summary of PM Reflective Symptom Scores for Eye Redness (Population: ITT)

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7.76

Analysis of Mean Change from Baseline In PM Reflective Symptom Scores for Eye Redness (Population: ITT)

7.77

Summary of Daily Peak Nasal Inspiratory Flow (Population: ITT)

7.78

Analysis of Mean Change from Baseline In Daily Peak Nasal Inspiratory Flow (Population: ITT)

7.79

Summary of AM Peak Nasal Inspiratory Flow (Population: ITT)

7.80

Analysis of Mean Change from Baseline In AM Peak Nasal Inspiratory Flow (Population: ITT)

7.81

Summary of PM Peak Nasal Inspiratory Flow (Population: ITT)

7.82

Analysis of Mean Change from Baseline In PM Peak Nasal Inspiratory Flow (Population: ITT)

7.83

Summary of AM Pre-Dose Instantaneous Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.84

Analysis of Mean Change from Baseline in AM Pre-Dose Instantaneous Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.85

Summary of Daily Reflective Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.86

Analysis of Mean Change from Baseline in Daily Reflective Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.87

Summary of AM Reflective Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.88

Analysis of Mean Change from Baseline in AM Reflective Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.89

Summary of PM Reflective Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.90

Analysis of Mean Change from Baseline in PM Reflective Total Nasal Symptom Scores – Days 1 to 28 (Population: ITT)

7.91

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Age 12 to 17 Years)

7.92

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Age 18 to 64 Years)

7.93

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Age ≥65 Years) 36

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7.94

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/USA)

7.95

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Canada)

7.96

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Estonia)

7.97

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/ Slovakia)

7.98

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Germany)

7.99

Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Hungary)

7.100 Summary of Daily Reflective Total Nasal Symptom Scores (Population: ITT/Russia) Safety

8.1

Summary of Extent of Exposure to Study Medication (Population: ITT)

8.2

Listing of Exposure Data (Population: ITT)

8.3

Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text

8.4

Summary of All Adverse Events During the Screening Period (Population: ITT)

8.5

Summary of All Adverse Events During the Treatment Period (Population: ITT)

8.6

Summary of Adverse Events with Incidence Rate >3% and More Common than Placebo During the Treatment Period (Population: ITT)

8.7

Summary of Adverse Events with Incidence Rate of 1% to 3% and More Common than Placebo During the Treatment Period (Population: ITT)

8.8

Summary of All Adverse Events During the Post-Treatment Period (Population: ITT)

8.9

Listing of Subject Numbers for Individual Adverse Events (Population: ITT)

8.10

Listing of All Adverse Events During the Study Period (Population: ITT)

8.11

Listing of All Adverse Events During the Study Period Sorted by Preferred Term (Population: ITT)

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8.12

Summary of Drug-Related Adverse Events During the Study Period (Population: ITT)

8.13

Listing of Drug-Related Adverse Events During the Study Period (Population: ITT)

8.14

Listing of Serious Adverse Events During the Screening Period (Population: Screen Failure)

8.15

Listing of Serious Adverse Events During the Study Period (Population: ITT)

8.16

Summary of Adverse Events Causing Withdrawal from the Study (Population: ITT)

8.17

Listing of Adverse Events Causing Withdrawal from the Study (Population: ITT)

8.18

Summary of All Adverse Events During the Treatment Period (Population: ITT/Age 12 to 17 Years)

8.19

Summary of All Adverse Events During the Treatment Period (Population: ITT/Age 18 to 64 Years)

8.20

Summary of All Adverse Events During the Treatment Period (Population: ITT/Age ≥65 Years)

8.21

Summary of All Adverse Events During the Treatment Period (Population: ITT/Female)

8.22

Summary of All Adverse Events During the Treatment Period (Population: ITT/Male)

8.23

Definitions of Normal Ranges for Laboratory Values

8.24

Summary of Laboratory Data (Population: ITT)

8.25

Summary of Laboratory Data Outside the Normal Range (Population: ITT)

8.26

Summary of Laboratory Shifts (Population: ITT)

8.27

Listing of Laboratory Data for Subjects with at Least One Abnormal Value in Hematology (Population: ITT)

8.28

Listing of Laboratory Data for Subjects with at Least One Abnormal Value in Chemistry (Population: ITT)

8.29

Summary of Nasal Examinations (Population: ITT)

8.30

Summary of Nasal Examination Shifts (Population: ITT)

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8.31

Listing of Subjects With at Least One Occurrence of Worsening Ulcers at Any Time Post-Baseline (Population: ITT)

8.32

Listing of Subjects With at Least One Occurrence of Worsening Mucosal Bleeding at Any Time Post-Baseline (Population: ITT)

8.33

Listing of Subjects with an at Least One Abnormal Nasal Examination Result Post-Baseline (Population: ITT)

8.34

Listing of Subjects with Clinical Evidence of Nasal Candidiasis (Population: ITT)

8.35

Summary of Vital Signs (Population: ITT)

8.36

Summary of Change from Baseline in Vital Signs (Population: ITT)

Health Outcomes

9.1

Summary of RQLQ(S) Scores (Population: ITT)

9.2

Analysis of Mean Change from Baseline to Endpoint in RQLQ(S) Scores (Population: ITT)

16.2.

Data Display Specifications

Data display Specification data will be available on request.

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Synopsis Identifier: RM2008/00422/00 Study Number: FFU111439 Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) Investigators: This was a multicenter study. Study centers: A total of 34 investigational sites randomized subjects: 12 in the United States (US), 10 in Canada, 3 in Germany, 3 in Hungary, 3 in the Russian Federation, 2 in Estonia, and 1 in Slovakia. Publication(s): None at the time of this report. Study Period: 25Jan2008 - 26Jun2008 Phase of Development: IV Objectives: The objective of this study was to compare the efficacy and safety of fluticasone furoate nasal spray 110mcg once daily with vehicle placebo nasal spray in subjects with PAR, 12 years of age and older. Methodology: This was a 4-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Following a 7- to 14-day screening period, subjects meeting randomization criteria were randomized to 4 weeks of treatment with fluticasone furoate nasal spray 110 mcg once daily or placebo nasal spray. Subjects were scheduled to return to the clinic at the end of each week for 4 weeks during the treatment period. Throughout the study, subjects rated their nasal and ocular symptoms of allergic rhinitis and peak nasal inspiratory flow (PNIF) and recorded them on an electronic diary. A follow-up phone call for adverse event (AE) assessment was made 3 to 5 days after the last clinic visit. Number of subjects: The planned sample size was 288 subjects. A total of 315 subjects were randomized, 160 in the fluticasone furoate 110 mcg group and 155 in the placebo group. Diagnosis and main criteria for inclusion: Male and female subjects were eligible for treatment as outpatients if they had a diagnosis of perennial allergic rhinitis and were ≥12 years at Visit 2 for Canada, Estonia, Hungary, Slovakia, and the US; ≥18 years at Visit 1 for Germany and Russia. Subjects must have been symptomatic to appropriate perennial allergens such as animal dander, house dust mites, cockroach, and mold and must have had a positive skin prick test.

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Treatment administration: Subjects were randomized to 4 weeks of treatment with either once-daily fluticasone furoate 110 mcg nasal spray or placebo nasal spray. Subjects were instructed to administer two sprays into each nostril once daily every morning. Administration of the dose was performed by alternately spraying one spray to each nostril followed by a second spray to each nostril. The first dose of study drug was self-administered in the clinic before noon at Visit 2 (Randomization Visit). The lot numbers for fluticasone furoate 110 mcg nasal spray treatment and placebo nasal spray treatment were and respectively. Criteria for evaluation: Efficacy endpoints: All efficacy measures for nasal symptoms (rhinorrhea, nasal congestion, nasal itching, sneezing) and ocular symptoms (eyes itching/burning, eyes tearing/watering, and eye redness) were based on subject-rated, individual symptom assessments as evaluated on a 4-point (0-3) categorical scale, recorded on an electronic diary. All efficacy endpoints reflected the change over the entire treatment period. Primary Efficacy Endpoint: •

Mean change from baseline over the entire treatment period in daily, reflective, total nasal symptom scores (rTNSS)

The rTNSS is equal to the sum of the 4 individual nasal symptom score assessments for rhinorrhea, nasal congestion, nasal itching, and sneezing, where each symptom is scored on a scale of 0 to 3. Key Secondary Efficacy Endpoints: •

Mean change from baseline over the entire treatment period in morning (AM), predose, instantaneous total nasal symptom scores (iTNSS)

The AM pre-dose iTNSS is the sum of the 4 individual nasal symptom score assessments for rhinorrhea, nasal congestion, nasal itching, and sneezing performed at the moment immediately prior to taking their dose. •

Mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS)

The rTOSS is equal to the sum of the 3 individual ocular symptom scores for eye itching/burning, eye tearing/watering, and eye redness.

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Other Secondary Efficacy Endpoints: Total Nasal Symptoms •

Mean change from baseline over the entire treatment period in AM rTNSS and evening (PM) rTNSS;

•

Mean percentage change from baseline over the entire treatment period in daily rTNSS and AM, pre-dose iTNSS.

Individual Nasal Symptoms •

Mean change from baseline over the entire treatment period in both individual daily reflective and AM pre-dose instantaneous nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing;

•

Mean change from baseline over the entire treatment period in individual AM and PM reflective nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing.

Total Ocular Symptoms •

Mean change from baseline over the entire treatment period in AM, pre-dose, instantaneous, total ocular symptom scores (iTOSS);

•

Mean change from baseline over the entire treatment period in AM rTOSS and PM rTOSS;

•

Mean percent change from baseline over the entire treatment period in daily rTOSS and AM pre-dose iTOSS.

Individual Ocular Symptoms •

Mean change from baseline over the entire treatment period in both individual daily reflective and AM pre-dose instantaneous ocular symptom scores for eyes itching/burning, eyes tearing/watering, and eye redness;

•

Mean change from baseline over the entire treatment period in individual AM and PM reflective ocular symptom scores for eyes itching/burning, eyes tearing/watering, and eye redness.

Peak Nasal Inspiratory Flow (PNIF) •

Mean change from baseline over the entire treatment period in daily, AM and PM PNIF.

Safety Endpoints: •

Frequency and type of clinical AEs;

•

Clinical laboratory tests (hematology and chemistry);

•

Nasal examinations (mucosal bleeding, ulcers, polyps, and fungal infections);

•

Vital signs (systolic and diastolic blood pressure and heart rate [pulse]). - 33 -

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Health Outcomes Endpoint: Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities (RQLQ[S]) Statistical methods: The primary analysis method was the comparison of treatment groups (fluticasone furoate 110 mcg versus placebo) using analysis of covariance (ANCOVA), adjusting for baseline daily rTNSS, country, age, and gender. The secondary efficacy measures of nasal symptoms, ocular symptoms, and PNIF data were analyzed in a similar manner to the primary efficacy analysis. The analysis method was the comparison of fluticasone furoate 110 mcg versus placebo using ANCOVA adjusting for baseline value, country, age, and gender. The multiple comparisons between fluticasone furoate 110 mcg nasal spray and placebo for the key secondary efficacy and health outcomes endpoints were performed, in sequence (mean change in AM pre-dose iTNSS, mean change in daily rTOSS, and mean change in RQLQ[S] global score), with the primary efficacy endpoint as the gatekeeper, to control the overall significance level of 0.05. No multiplicity adjustments were made on the other secondary efficacy or health outcomes endpoints. Any p-values ≤0.05 were identified as nominally significant. A total of 288 subjects were required for this study, with 144 subjects in each of the two treatment groups: fluticasone furoate 110 mcg nasal spray and placebo. The randomization was stratified by country to account for possible country effects on the study outcome due to country-specific medical practices. Data from previous GlaxoSmithKline studies suggested a reasonable assumption for the standard deviation of mean change from baseline over the entire treatment period in daily rTNSS would be 2.6. Using a two-sample t-test with a two-sided significance level of 0.05, the chosen sample size provided 90% power to detect a difference of 1.0 between active treatment and placebo. The efficacy, safety, and health outcomes analyses used the Intent-to-Treat (ITT) population. The ITT population is defined as all randomized subjects who received at least one dose of study drug. Summary: Subject Disposition A total of 96% of subjects completed the study. The rate of early withdrawal was similar in both treatment groups. The most common reason for early withdrawal was protocol deviation (e.g., failed to meet minimum symptom randomization criteria or exclusion criteria deviation).

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FFU111439

Subject Disposition:

Completion Status Completed Not Completed Reason for discontinuation Adverse event Lack of efficacy Protocol deviation Lost to follow-up Withdrew consent

Placebo (N=155)

n (%) subjects FF 110 mcg (N=160)

Total (N=315)

148 (95) 7 (5)

153 (96) 7 (4)

301 (96) 14 (4)

1 (<1) 0 3 (2) 1 (<1) 2 (1)

1 (<1) 0 5 (3) 0 1 (<1)

2 (<1) 0 8 (3) 1 (<1) 3 (<1)

Efficacy For the primary efficacy endpoint of mean change from baseline over the entire treatment period in daily rTNSS, the reduction was inferentially significantly greater for once-daily fluticasone furoate 110 mcg nasal spray compared with placebo (LS mean difference: -0.741, p=0.004). In support of the primary endpoint, the Least Squares (LS) mean treatment differences for AM rTNSS and PM rTNSS were significantly greater for fluticasone furoate 110 mcg compared with placebo (AM, LS mean difference: -0.746, p=0.003; PM, LS mean difference: -0.758, p=0.004). The treatment difference between fluticasone furoate 110 mcg and placebo was also inferentially significantly different (in favor of fluticasone furoate 110 mcg) for the key secondary endpoint of mean change from baseline in AM pre-dose iTNSS (LS mean difference: -0.685, p=0.010) but was not significant for the key secondary endpoint of mean change from baseline in daily rTOSS (LS mean difference: -0.240, p=0.243).

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Primary and Key Secondary Endpoints: Weeks 1-4a Daily rTNSS (Primary) Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb AM Pre-dose iTNSS (Key Secondary) Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb Daily rTOSS (Key Secondary) Mean Change (SE) LS Mean Change (SE)b LS Mean Differenceb p-valueb 95% CIb

Placebo (N=155)

FF 110 mcg (N=160)

-2.2 (0.19) -2.45 (0.24) -

-3.0 (0.19) -3.19 (0.23) -0.741 0.004 -1.24, -0.24

-2.1 (0.20) -2.29 (0.25) -

-2.8 (0.19) -2.97 (0.24) -0.685 0.010 -1.20, -0.17

-1.9 (0.16) -1.99 (0.20) -

-2.0 (0.15) -2.23 (0.19) -0.240 0.243 -0.64, 0.16

a = entire treatment period; b = based on ANCOVA adjusting for baseline values, country, age, and gender SE = Standard error; LS = Least square; CI = Confidence Interval; LS mean difference = LS mean change in active – LS mean change in placebo

A significant difference in favor of fluticasone furoate 110 mcg was also seen for all other secondary nasal endpoints. No significant differences were seen between the two treatments in daily rTOSS or any secondary endpoints related to ocular symptoms. Improvements in daily PNIF over the entire treatment period were significantly greater in the fluticasone furoate 110 mcg group compared with the placebo group (LS mean difference = 6.458 L/min, p=0.007). The LS mean treatment differences for AM and PM PNIF were also significantly greater for fluticasone furoate 110 mcg compared with placebo (AM, LS mean difference: 6.520 L/min, p=0.008; PM, LS mean difference: 6.175 L/min, p=0.013). Onset of treatment effect was observed by Day 9 after the first dose based on AM predose iTNSS and Day 8 based on daily rTNSS and was maintained during the 4-week treatment period, except for Days 10 and 13 (AM pre-dose iTNSS) and Days 10, 12, 13, and 28 (daily rTNSS). The greatest LS mean difference between the two treatments in daily rTNSS (maximum effect) occurred on Day 22 (-1.230, p<0.001).

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Safety The mean number of days of exposure was similar for both treatment groups (28.5 and 28.6 days for the fluticasone furoate 110 mcg and placebo groups, respectively). During the treatment period, the incidence of AEs was 42% in the fluticasone furoate 110 mcg group and 34% in the placebo group. The most common AE was epistaxis, with incidence rates of 15% and 8% in the fluticasone furoate 110 mcg and placebo groups, respectively; all instances of epistaxis were mild in intensity. By study end, all instances of epistaxis had completely resolved, except for three events in the fluticasone furoate 110 mcg group and two events in the placebo group that were reported at the final visit. The only other AE reported as occurring at a greater than 3% incidence and more common than placebo was nasopharyngitis, which had incidence rates of 5% and 1% in the fluticasone furoate 110 mcg and placebo groups, respectively. The most common drug-related AE was epistaxis, which occurred at incidence rates of 12% in the fluticasone furoate 110 mcg group and 4% in the placebo group. One subject each in the fluticasone furoate 110 mcg and placebo groups withdrew from the study because of AEs; these were not considered to be drug related. The AE leading to withdrawal from the study in the fluticasone furoate 110 mcg group had an onset during the screening period. No fatal or non-fatal SAEs occurred during the study. One pregnancy was reported in the placebo group during the study; the outcome was unknown at the time of reporting. The incidence of laboratory abnormalities was low and similar between the two treatment groups. Findings from the nasal examinations were similar for the two treatment groups, with the exception of a higher incidence in the fluticasone furoate 110 mcg group at Week 4 of polyps (3% and <1% for the fluticasone furoate 110 mcg and placebo groups, respectively) and of ulcers on the turbinates/septum (1% and none for the fluticasone furoate 110 mcg and placebo groups, respectively). The incidence of mucosal bleeding was greater in the fluticasone furoate 110 mcg group (6%) than in the placebo group (<1%) by the end of the study. Changes in vital signs were minor and similar across the two treatment groups.

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Adverse Events Occurring at ≥1% Incidence and More Common than Placebo:

Subjects with any AE Epistaxis Nasopharyngitis Scaba Arthralgia Cough Pharyngolaryngeal pain Upper respiratory tract infection Bronchitis Nasal ulcer Nausea Respiratory tract infection viral Viral infection Toothache a.

Placebo (N=155) n (%) 52 (34) 13 (8) 2 (1) 3 (2) 1 (<1) 2 (1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 0 1 (<1) 0

FF 110 mcg (N=160) n (%) 67 (42) 24 (15) 8 (5) 4 (3) 4 (3) 3 (2) 3 (2) 3 (2) 2 (1) 2 (1) 2 (1) 3 (2) 2 (1) 2 (1)

System Organ Class = Skin and subcutaneous tissue disorders

Pharmacogenetics During the course of the study, 239 (76%) subjects provided blood samples for deoxyribonucleic acid (DNA) extraction and pharmacogenetic analysis (PGx). No analysis of the PGx samples is currently planned. Health Outcomes Subjects assigned to fluticasone furoate 110 mcg once daily experienced a significant improvement compared with placebo for the overall RQLQ(S) score (LS mean difference: -0.537, p=0.028) and for 4 of the 7 individual domains: Activities (LS mean difference: -0.595, p=0.028), Sleep (LS mean difference: -0.751, p=0.010), NonNose/Eye Symptoms (LS mean difference: -0.614, p=0.014), and Nasal Symptoms (LS mean difference:-0.592, p=0.031). There also was a minimally important difference (greater improvement of at least 0.5 over placebo) in the fluticasone furoate 110 mcg group for the overall RQLQ(S) score and for these 4 individual domains. The difference between treatment groups was not significant for three individual domains: Practical Problems (LS mean difference: -0.569, p=0.058), Eye Symptoms (LS mean difference: 0.374, p=0.174), and Emotional (LS mean difference: -0.480, p=0.077).

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Conclusions: •

Once-daily fluticasone furoate 110 mcg nasal spray demonstrated inferentially significantly greater improvements (LS mean difference: -0.741, p=0.004) in the nasal symptoms of PAR versus placebo nasal spray in adult and adolescent subjects 12 years of age and older based on the primary endpoint of daily rTNSS (rhinorrhea, nasal congestion, nasal itching, sneezing) over 4 weeks of treatment. In support of the primary endpoint, the LS mean treatment differences for the AM rTNSS and PM rTNSS were also significant for fluticasone furoate 110 mcg (AM, LS mean difference: -0.746, p=0.003; PM, LS mean difference: -0.758, p=0.004).

•

Use of fluticasone furoate 110 mcg nasal spray once daily resulted in an inferentially significant mean difference between the two treatments in AM pre-dose iTNSS reduction over the treatment period (LS mean difference = -0.685, p=0.010). ). A significant difference in favor of fluticasone furoate 110 mcg was also seen for all other secondary nasal endpoints.

•

Use of fluticasone furoate 110 mcg nasal spray once daily did not result in a significant difference between the two treatments in daily rTOSS over the treatment period (LS mean difference = -0.240, p=0.243). Fluticasone furoate 110 mcg did not demonstrate significant improvements in any secondary endpoints related to ocular symptoms over the treatment period.

•

Improvements in daily PNIF over the entire treatment period were significantly greater in the fluticasone furoate 110 mcg group compared with the placebo group (LS mean difference = 6.458 L/min, p=0.007).

•

Onset of treatment effect was observed by Day 9 after the first dose based on AM pre-dose iTNSS and Day 8 based on daily rTNSS and was maintained during the 4-week treatment period, except for Days 10 and 13 (AM pre-dose iTNSS) and Days 10, 12, 13, and 28 (daily rTNSS). The greatest LS mean difference between the two treatments in daily rTNSS (maximum effect) occurred on Day 22 (-1.230, p<0.001).

•

Four weeks of treatment with fluticasone furoate 110 mcg resulted in significant improvement in quality of life compared with placebo based on the overall RQLQ(S) score (LS mean difference: -0.537, p=0.028) and for 4 of the 7 individual domains: Activities (LS mean difference: -0.595, p=0.028), Sleep (LS mean difference: -0.751, p=0.010), Non-Nose/Eye Symptoms (LS mean difference: -0.614, p=0.014), and Nasal Symptoms (LS mean difference:-0.592, p=0.031). There also was a minimally important difference (greater improvement of at least 0.5 over placebo) in the fluticasone furoate 110 mcg group for the overall RQLQ(S) score and for these 4 individual domains. The difference between treatment groups was not significant for three individual domains: Practical Problems, Eye Symptoms, and Emotional.

•

During the treatment period, the incidence of AEs was 42% in the fluticasone furoate 110 mcg group and 34% in the placebo group. The only AEs to occur at a greater than 3% incidence and more common than placebo were epistaxis (15% and 8%) and nasopharyngitis (5% and 1%) in the fluticasone furoate 110 mcg group and the placebo group, respectively.

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•

No safety issues were identified with findings from vital signs and laboratory values being similar for the two treatment groups.

•

Findings from the nasal examinations were similar for the two treatment groups, except for an increase in the incidence of mucosal bleeding following 4 weeks treatment with fluticasone furoate 110 mcg compared with placebo. The incidence of mucosal bleeding increased from 3% to 6% for fluticasone furoate 110 mcg subjects and decreased from 1% to <1% for placebo subjects from randomization to Week 4.

•

The results of this study support the once-daily use of fluticasone furoate 110 mcg nasal spray in adult and adolescent subjects 12 years of age and older for the treatment of symptoms of PAR.

Date of Report: November 2008

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RM2007/00519/00 CONFIDENTIAL CONFIDENTIAL The GlaxoSmithKline group of companies GlaxoSmithKline group of companies

RM2008/00422/00 RM2007/00519/00 FFU111439 FFU111439

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Protocol Title:

A Randomized, Double-Blind, Placebo-Controlled, ParallelGroup, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR)

Compound Number: GW685968X Development Phase

IV

Effective Date:

25-OCT-2007

Description: The primary objective of this study is to compare the efficacy and safety of 4-weeks treatment with fluticasone furoate 110mcg once daily (QD) and placebo vehicle nasal sprays in subjects ≥12 years of age with perennial allergic rhinitis (PAR). The study will be conducted in North America and Europe. Approximately 40 - 50 investigative sites will randomize approximately 288 subjects. After completing a 7 to 14 -day screening period, eligible subjects will be randomized in a 1:1 ratio to receive either fluticasone furoate nasal spray (FFNS) QD or vehicle placebo nasal spray QD. Subjects will make six clinic visits during the study period. A follow-up telephone contact will be made to subjects 3 to 5 days after the last treatment visit (Visit 6) or Early Withdrawal Visit to assess for any post-treatment adverse events. All efficacy measures will be based on subject self-assessments. The primary efficacy measure for the study will be the mean change from baseline over the entire treatment period in daily, reflective, total nasal symptom scores (rTNSS). Key secondary measures will be the mean change from baseline over the entire treatment period in morning, pre-dose, instantaneous, total nasal symptom scores (iTNSS) and the mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS). Peak Nasal Inspiratory Flow (PNIF) will be measured throughout the study. A health outcomes questionnaire, the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ(S)], will also be administered at the randomization visit and the final visit. Safety measures include adverse event reporting, clinical laboratory tests (hematology and chemistry), vital signs, physical examinations and nasal examinations. Subject compliance will be assessed by subjects completing daily electronic diaries twice daily. Subject: Perennial Allergic Rhinitis, fluticasone furoate nasal spray, GW685698X Author(s): Copyright 2007 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. -1-

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SPONSOR INFORMATION PAGE Clinical Study Identifier:

FFU111439

Sponsor Contact Information: MA, BM, BCh Telephone: Fax: GlaxoSmithKline Building 11, Stockley Park West Uxbridge, Middlesex UB11 1BT Telephone: MD Telephone: Fax: GlaxoSmithKline Five Moore Drive P.O. 13398 Research Triangle Park, NC 27709-3398, USA Telephone: In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission. Sponsor Serious Adverse Events (SAE) Contact Information: Case Management Group, Global Clinical Safety and Pharmacovigilance Telelphone: Fax: Regulatory Agency Identifying Number(s): 48,647 EudraCT Number: 2007-005136-89

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INVESTIGATOR PROTOCOL AGREEMENT PAGE I confirm agreement to conduct the study in compliance with the protocol.

Investigator Name: _____________________________

Investigator Signature

Date

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INFORMATION FOR CLINICALTRIALS.GOV Title A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR)

Purpose The objective of this study is to compare the efficacy and safety of FFNS 110mcg QD with vehicle placebo nasal spray in subjects with PAR, 12 years of age and older. The study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study, and will include approximately 288 randomized subjects.

Eligibility Criteria •

Male and female outpatients 12 years of age and older

•

Diagnosis of perennial allergic rhinitis (PAR)

Location and Contact Information This study will be conducted in North America and Europe.

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TABLE OF CONTENTS

ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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PROTOCOL SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. RATIONALE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15 15 16

2. OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16

3. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. STUDY DESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. DISCUSSION OF DESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16 16 18

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA . . . . . . . . . . . . . . . . . . . 4.1. NUMBER OF SUBJECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. INCLUSION CRITERIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. RANDOMIZATION CRITERIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. EXCLUSION CRITERIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. SCREEN FAILURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. WITHDRAWAL CRITERIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18 18 18 20 20 23 23

5. STUDY TREATMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. INVESTIGATIONAL PRODUCT AND REFERENCE THERAPY . . . . . . . . 5.2. TREATMENT ASSIGNMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. BLINDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. PRODUCT ACCOUNTABILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. TREATMENT COMPLIANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES . . . . . . . 5.6.1. Permitted Medications and Non-Drug Therapies . . . . . . . . . . . . . . . 5.6.2. Prohibited Medications and Non-Drug Therapies . . . . . . . . . . . . . . . 5.7. TREATMENT AFTER THE END OF THE STUDY . . . . . . . . . . . . . . . . . . . 5.8. TREATMENT OF INVESTIGATIONAL PRODUCT OVERDOSE . . . . . . . .

24 24 26 26 27 27 28 28 28 29 29

6. STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. CRITICAL BASELINE ASSESSMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. EFFICACY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Primary Efficacy Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Secondary Efficacy Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.3. Assessments Recorded on Electronic Diaries . . . . . . . . . . . . . . . . . . 6.2.4. Nasal Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.5. Ocular Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6.2.6. Peak Nasal Inspiratory Flow (PNIF) . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1. Safety Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. Medical History and Concomitant Drug Use . . . . . . . . . . . . . . . . . . . 6.3.3. Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.4. Nasal Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.5. Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.6. Clinical Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.7. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.8. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.9. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.10. Time Period and Frequency of Detecting AEs and SAEs . . . . . . . . 6.3.11. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.12. Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.13. Prompt Reporting of Serious Adverse Events and Other Events to GSK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. HEALTH OUTCOMES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.1. Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ (S)] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. PHARMACOGENETICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35 35 35 35 35 36 36 36 37

7. DATA MANAGEMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . 8.1. HYPOTHESES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. STUDY DESIGN CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.1. Sample Size Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.2. Sample Size Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.3. Sample Size Re-estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. DATA ANALYSIS CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.1. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.2. Analysis Data Sets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.3. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.4. Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.5. Key Elements of Analysis Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45 45 46 46 46 46 47 47 47 47 50 50

9. STUDY CONDUCT CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING THE INFORMED CONSENT PROCESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. QUALITY CONTROL (STUDY MONITORING) . . . . . . . . . . . . . . . . . . . . . . 9.3. QUALITY ASSURANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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9.4. STUDY AND SITE CLOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5. RECORDS RETENTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.6. PROVISION OF STUDY RESULTS AND INFORMATION TO INVESTIGATORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.7. INDEPENDENT DATA MONITORING COMMITTEE (IDMC) . . . . . . . . . . .

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10. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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11. APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1. APPENDIX 1: PGX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2. Appendix 2: Clinical Laboratory Assessments . . . . . . . . . . . . . . . . . . . . . . 11.3. APPENDIX 3: COUNTRY-SPECIFIC REQUIREMENTS . . . . . . . . . . . . .

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ABBREVIATIONS AE ALT AM AST CHMP CI CRF DNA ECG eCRF e-diary EDTA EW FDA FFNS GCP GINA GSK IDMC IEC IgE IND IRB iTNSS iTOSS ITT IUD IUS IVRS mcg MSDS NAEPP OTC PAR PGx PIN PM PNIF PRIST QC QD RAMOS RAST

Adverse Event Alanine aminotranferease Ante Meridiem (before midday) Aspartate aminotransferase Committee for Medicinal Products for Human Use Confidence Intervals Case Report Form deoxyribonucleic acid Electrocardiogram Electronic case report form Electronic diary Ethylenediaminetetraacetic acid Early withdrawal Food and Drug Administration Fluticasone Furoate Nasal Spray Good Clinical Practice Global Initiative for Asthma GlaxoSmithKline Independent Data Monitoring Committee Independent ethic committee Immunoglobulin E Investigational New Drug Institutional Review Board Instantaneous total nasal symptom score Instantaneous total ocular symptom score Intend-to-treat Intrauterine device Intrauterine system Interactive Voice Response System micrograms Material Safety Data Sheet National Asthma Education and Prevention Program Over-the-counter Perennial Allergic Rhinitis Pharmacogenetics Personal identification number Post Meridiem (after midday) Peak Nasal Inspiratory Flow Paper Radioimmunosorbent Test Quality control Once daily Registration and Medication Ordering System RadioAllergoSorbent Test

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RQLQ(S) rTNSS rTOSS SAE SNP SOC SPM TNSS TOSS UK ULN US w/w

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Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities Reflective total nasal symptom score Reflective total nasal symptom score Serious adverse event single nucleotide polymorphism System organ class Study Procedures Manual Total nasal symptom score Total ocular symptom score United Kingdom Upper limit of normal United States Weight per weight

Trademark Information Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

FLONASE SEREVENT VERAMYST ZANTAC

Allegra Astelin Atrovent Axid Benadryl Chlortrimeton Clarinex Claritin Crolom Dimetane Foradil In-Check Nasal Miacalcin Nasalcrom Nasonex Pepcid Rhinocort Singulair Sudafed Tagamet Tavist Xolair Zyrtec

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PROTOCOL SUMMARY Rationale The safety and efficacy of fluticasone furoate nasal spray (FFNS) 110mcg once daily (QD) have been established in two Phase 3 perennial allergic rhinitis (PAR) studies (FFR30002, 4-week treatment; and FFR106080, 6-week treatment). The current PAR study is being conducted to determine the efficacy of FFNS for the treatment of ocular symptoms associated with PAR.

Objective(s) The objective of this study is to compare the efficacy and safety of FFNS 110mcg QD with vehicle placebo nasal spray in subjects with PAR, 12 years of age and older.

Study Design This is a 4-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to be conducted in North America and Europe. Approximately 40 - 50 investigative sites will randomize approximately 288 subjects. Subjects who satisfy the entry criteria will enter a screening period (Visit 1) consisting of a minimum of 7 days and a maximum of 14 days. During the screening period subjects will score their symptoms on an electronic diary (e-diary) in order to determine eligibility for randomization. After a minimum of 7 days, subjects who fulfil the randomization criteria will be randomly assigned in a 1:1 ratio to one of the following two intranasal, double-blind groups to self-administer treatment for 28 days (4 weeks): Fluticasone furoate nasal spray (FFNS) 110mcg QD Vehicle placebo nasal spray QD The first dose of study drug will be administered in the clinic prior to noon at Visit 2 to randomized subjects to allow time for subjects to perform a 12-hour efficacy assessment prior to bedtime. Subjects will be instructed to administer two sprays of study medication per nostril each morning. Subjects will return to the clinic at the end of each week for four weeks (Visits 3 – 6) during the treatment period. All clinic visits should be made within ± 3 days of scheduled visits. NOTE: Subject clinic visits should be scheduled to occur based on the date of Visit 2 (Randomization). The double-blind treatment period should not exceed 32 days. Subjects will be instructed not to take any anti-allergy/anti-rhinitis medication during the screening or treatment study periods. No allergy rescue medication will be allowed throughout the entire study period.

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Throughout the study, subjects will rate their nasal and ocular symptoms of allergic rhinitis and record them on the e-diary. Subjects will also document study drug administration/compliance, peak nasal inspiratory flow (PNIF) readings, medical conditions experienced and concomitant medications taken. All subjects will be outpatients. Clinic visits will be scheduled to occur at the following intervals: Visit 1 Screening (7 to 14 days prior to randomization) Visit 2 Randomization (Day 1) Visit 3 (7 ± 3 days after Visit 2, Day 8) Visit 4 (14 ± 3 days after Visit 2, Day 15) Visit 5 (21 ± 3 days after Visit 2, Day 22) Visit 6 (28 ± 3 days after Visit 2, Day 29) A follow-up telephone contact will be made 3 to 5 days after Visit 6 or Early Withdrawal Visit to assess for any post-treatment adverse events. A subject that remains in the study throughout the screening and treatment periods to Visit 6 and receives double-blind treatment for the 4-week treatment period is considered to have completed the study. Any subject who withdraws prior to Visit 6 will be considered an early withdrawal.

Study Endpoints/Assessments All efficacy measures for nasal (rhinorrhea, nasal congestion, nasal itching, sneezing) symptoms and ocular symptoms (eye itching/ burning, eye tearing/watering, and eye redness) are based on subject-rated, individual symptom assessments as evaluated on a 4 point (0-3) categorical scale, recorded on an e-diary. Efficacy measures for the peak nasal inspiratory flow (PNIF) are also based on the subject twice-daily assessments using an In-Check portable hand-held nasal inspiratory flow meter and face mask (Clement-Clarke International, Harlow, UK), recorded on the e-diary. The primary endpoint of the study is the mean change from baseline over the entire treatment period in daily, reflective, total nasal symptoms scores (rTNSS). Key secondary endpoints are: •

Mean change from baseline over the entire treatment period in morning (AM), predose, instantaneous total nasal symptom scores (iTNSS)

•

Mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS)

Other secondary endpoints include:

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Total Nasal Symptoms •

Mean change from baseline over the entire treatment period in AM rTNSS

•

Mean change from baseline over the entire treatment period in PM rTNSS

•

Mean percent change from baseline over the entire treatment period in daily rTNSS

•

Mean percent change from baseline over the entire treatment period in AM, predose iTNSS

Individual Nasal Symptoms •

Mean change from baseline over the entire treatment period in individual, daily, reflective, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

•

Mean change from baseline over the entire treatment period in individual AM, pre-dose, instantaneous, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

•

Mean change from baseline over the entire treatment period in individual, AM, reflective, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

•

Mean change from baseline over the entire treatment period in individual, PM, reflective, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

Total Ocular Symptoms •

Mean change from baseline over the entire treatment period in AM, pre-dose, instantaneous, total ocular symptom scores (iTOSS)

•

Mean change from baseline over the entire treatment period in AM rTOSS

•

Mean change from baseline over the entire treatment period in PM rTOSS

•

Mean percent change from baseline over the entire treatment period in daily rTOSS

•

Mean percent change from baseline over the entire treatment period in AM, predose iTOSS

Individual Ocular Symptoms •

Mean change from baseline over the entire treatment period in individual, daily, reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, and eye redness

•

Mean change from baseline over the entire treatment period in individual AM, pre-dose, instantaneous, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness

•

Mean change from baseline over the entire treatment period in individual AM, reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness - 13 -

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Mean change from baseline over the entire treatment period in individual PM reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness

Peak Nasal Inspiratory Flow (PNIF) •

Mean change from baseline over the entire treatment period in daily peak nasal inspiratory flow (PNIF)

•

Mean change from baseline over the entire treatment period in AM peak nasal inspiratory flow

•

Mean change from baseline over the entire treatment period in PM peak nasal inspiratory flow

Health outcomes measures will include the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities (RQLQ[S]). The primary comparison of interest for the RQLQ(S) is the mean change from baseline to endpoint in the global score. Safety endpoints will consist of evaluations of clinical adverse events, clinical laboratory tests (hematology and chemistry), nasal examinations (mucosal bleeding, ulcers, polyps, and fungal infections), and vital signs.

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1.

INTRODUCTION

1.1.

Background

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Allergic rhinitis is an Immunoglobulin E (IgE)-mediated, inflammatory disorder of the upper airway that occurs following allergen exposure. Perennial Allergic Rhinitis (PAR) is a type of allergic rhinitis that is triggered by allergens year-round. The allergens that cause PAR are part of most household environments including animal dander from household pets, house dust mites, cockroach and mold spores. Intranasal corticosteroids are highly effective medications for controlling the nasal and ocular symptoms that accompany allergic rhinitis. The importance of their place in treatment has been recognized by The American Academy of Allergy, Asthma, and Immunology, which now considers them first line therapy when nasal congestion is a major component of the allergic rhinitis patient’s presentation [AAAAI, 2000]. While the exact pharmacological mechanism of intranasal corticosteroids is unknown, these medications are known to reduce vascular permeability and oedema of the nasal mucosa through inhibitory effects on inflammatory cells and mediator activity. Fluticasone furoate nasal spray (FFNS) is a novel corticosteroid with potent glucocorticoid activity. Because of its efficacy and low bioavailability (the absolute bioavailability of FFNS in healthy volunteers is on average 0.50%), fluticasone furoate has been developed as an intranasal aqueous nasal spray for this disease [Allen, 2007]. The safety and efficacy of FFNS for the symptoms of seasonal and perennial allergic rhinitis have been demonstrated during the Phase 3 clinical development program. In April 2007, fluticasone furoate nasal spray (tradename VERAMYST™), was approved by the US Food and Drug Administration (FDA) for the treatment of symptoms of seasonal and perennial allergic rhinitis in adults and children ≥2 years [GlaxoSmithKline Document Number RM2004/00130/02, 2006 Investigator’s Brochure for GW685698X; VERAMYST Prescribing Information, 2007]. As an objective measure of nasal airway patency and obstruction, Peak Nasal Inspiratory Flow (PNIF) rates will be collected and recorded by the subjects on daily electronic diaries twice-a-day. PNIF has been used to evaluate medical and non-medical therapies, and has also been used as an outcome measure in nasal challenge testing [Wilson, 2003]. Data have shown the sensitivity of this test and the close correlation with patients’ symptoms of blockage and other objective measures of nasal airway function [Wilson, 2003]. Wilson et al [Wilson, 2000] demonstrated a significant correlation between improvements in nasal symptoms and peak inspiratory flow. In addition, PNIF measurements may aid in the assessment of subjects who have impaired symptom perception [Starling-Schwanz, 2005]. The PNIF has been found to be more discriminative than symptom scores in detecting efficacy differences between doses [Bende, 2002].

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1.2.

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Rationale

The safety and efficacy of FFNS 110mcg QD have been established in two Phase 3 PAR studies (FFR30002, 4-week treatment; and FFR106080, 6-week treatment). The current PAR study is being conducted to determine the efficacy of FFNS for the treatment of ocular symptoms associated with PAR.

2.

OBJECTIVE(S)

The objective of this study is to compare the efficacy and safety of FFNS 110mcg QD with vehicle placebo nasal spray in subjects with PAR, 12 years of age and older.

3.

INVESTIGATIONAL PLAN

3.1.

Study Design

Figure 1 illustrates the study schematic. Figure 1

Study Schematic Randomization DOUBLE-BLIND TREATMENT GW685698X FFNSNasal 110 mcg Spray QD110 mcg QD (N = 144)) OR Placebo Nasal Spray (N = 144)

No Treatment

No Treatment

(Screening Period)

Visit 1 -14 to - 7 Days

(F/U Phone Call)

Visit 2 Day 1 ( Randomization)

Visits 3-6 Days 8 - 29

F/U Phone Call (3 -5 days following Visit 6 or EW)

This is a 4-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to be conducted in North America and Europe. Approximately 40 - 50 investigative sites will randomize approximately 288 subjects. Subjects who satisfy the entry criteria will enter a screening period (Visit 1) consisting of a minimum of 7 days and a maximum of 14 days. During the screening period subjects - 16 -

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will score their symptoms on an electronic diary (e-diary) in order to determine eligibility for randomization. After a minimum of 7 days, subjects who fulfil the randomization criteria will be randomly assigned in a 1:1 ratio to one of the following two intranasal, double-blind groups to self-administer treatment for 28 days (4 weeks): Fluticasone furoate nasal spray (FFNS) 110mcg QD Vehicle placebo nasal spray QD The first dose of study drug will be administered in the clinic prior to noon at Visit 2 to randomized subjects to allow time for subjects to perform a 12-hour efficacy assessment prior to bedtime. Subjects will be instructed to administer two sprays of study medication per nostril each morning. Subjects will return to the clinic at the end of each week for four weeks (Visits 3 – 6) during the treatment period. All clinic visits should be made within ±3 days of scheduled visits. NOTE: Subject clinic visits should be scheduled to occur based on the date of Visit 2 (Randomization). The double-blind treatment period should not exceed 32 days. Subjects will be instructed not to take any anti-allergy/anti-rhinitis medication during the screening or treatment study periods. No allergy rescue medication will be allowed throughout the entire study period. Throughout the study, subjects will rate their nasal and ocular symptoms of allergic rhinitis and record them on the e-diary. Subjects will also document study drug administration/compliance, peak nasal inspiratory flow (PNIF) readings, medical conditions experienced and concomitant medications taken. The subjects will be instructed to administer two sprays per nostril each morning. All subjects will be outpatients. Clinic visits will be scheduled to occur at the following intervals: Visit 1 Screening (7 to 14 days prior to randomization) Visit 2 Randomization (Day 1) Visit 3 (7 ± 3 days after Visit 2, Day 8) Visit 4 (14 ± 3 days after Visit 2, Day 15) Visit 5 (21 ± 3 days after Visit 2, Day 22) Visit 6 (28 ± 3 days after Visit 2, Day 29) A follow-up telephone contact will be made 3 to 5 days after Visit 6 or Early Withdrawal Visit to assess for any post-treatment adverse events. A subject that remains in the study throughout the screening and treatment periods to Visit 6 and receives double-blind treatment for the 4-week treatment period is considered

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to have completed the study. Any subject who withdraws prior to Visit 6 will be considered an early withdrawal. Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

3.2.

Discussion of Design

This study is being conducted primarily to collect additional ocular efficacy data for PAR subjects.

4.

SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1.

Number of Subjects

Approximately 288 subjects with a diagnosis of PAR who meet inclusion criteria will be randomized. The study will be stratified by country and will be centrally randomized within each country.

4.2.

Inclusion Criteria

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the investigational product that may impact subject eligibility is provided in the [GlaxoSmithKline Document Number RM2004/00130/02, 2006 Investigator’s Brochure for GW685698X; VERAMYST Prescribing Information, 2007]. Subjects eligible for enrollment in the study must meet all of the following criteria: 1.

2.

Informed consent •

Subject has provided an appropriately signed and dated informed consent.

•

An appropriately signed and dated assent must be obtained from the parents or guardian if the subject is a child under 18 years of age.

Outpatient •

3.

4.

Subject is treatable on an outpatient basis.

Age •

≥ 12 years at Visit 2

•

≥ 18 years at Visit 1 for Russia and Germany

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Female subjects should not be enrolled if they plan to become pregnant during the time of study participation. A urine pregnancy test will be performed for all females of childbearing potential at Visits 1, 2, 5, and Visit 6/Early Withdrawal to determine if the subject is pregnant. To be eligible for entry into the study, females of childbearing potential must commit to the consistent and correct use of an acceptable method of birth control, as defined by the following: •

Abstinence

Females of childbearing potential who are not sexually active must commit to complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of six days).

5.

•

Oral contraceptive (either combined estrogen/progestin or progestin only),

•

Injectable progestogen,

•

Implants of levonorgestrel,

•

Percutaneous contraceptive patches,

•

Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year,

•

Male partner who is sterile (vasectomy with documentation of azospermia) prior to the female subject’s entry into the study and is the sole sexual partner for that female subject,

•

Double barrier method–condom or occlusive cap (diaphragm or cervical /vault caps) plus spermicide,

•

Estrogenic vaginal ring

Diagnosis of PAR to include: •

A positive skin test (by prick method) response to appropriate perennial allergen (house dust mites, animal dander, mold, or cockroach) within last 12 months prior to Visit 1 or at Visit 1.

A positive skin test is defined as a wheal ≥3mm larger than the diluent control for prick testing. •

Two year medical history and past treatment of PAR (written or verbal confirmation) which includes perennial, i.e., year-round, symptoms. PAR symptoms would include nasal congestion, rhinorrhea, nasal itching and sneezing, eye itching/burning, eye tearing/watering, and eye redness.

In vitro tests for specific IgE (such as RAST, PRIST) will not be allowed for the diagnosis of PAR. NOTE: Subjects who meet the above criteria for PAR and who also have a history of allergy to a seasonal pollen that will be present in their geographic area during study participation are NOT eligible for randomization.

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6.

Subject must be symptomatic to appropriate perennial allergen (animal dander, house dust mites, cockroach, mold) and willing to maintain same environment throughout the study.

Ability to comply with study procedures •

8.

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Environment •

7.

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Subject understands and is willing, able and likely to comply with study procedures and restrictions.

Literate •

4.3.

Subject must be able to read, comprehend, and record information in English or native language.

Randomization Criteria

At Visit 2, the subject must meet the following criteria: 1.

Average of the last 8 rTNSS assessments (4 AM assessments, 4 PM assessments) over the four 24-hours periods prior to randomization must be ≥6. This includes the AM assessment on the morning of the randomization visit.

2.

Average of the last 8 reflective nasal symptom assessments for congestion (4 AM assessments, 4 PM assessments) over the four 24-hour periods prior to randomization must be ≥2. This includes the AM assessment on the morning of the randomization visit.

3.

Average of the last eight rTOSS assessments (4 AM assessments, 4 PM assessments) over the four 24-hour periods prior to randomization must be ≥ 4. This includes the AM assessment on the morning of the randomization visit.

4.

The subject has demonstrated the ability to comply with the use of the daily e-diary, defined as completion of at least 80% of the assessments during the screening period.

4.4.

Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled in the study: 1.

Significant concomitant medical conditions, defined as but not limited to: •

a historical or current evidence of clinically significant uncontrolled disease of any body system (e.g., tuberculosis, psychological disorders, eczema). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or which would confound the interpretation of the study results if the disease/condition exacerbated during the study.

•

a severe physical obstruction of the nose (e.g., deviated septum or nasal polyp) or nasal septal perforation that could affect the deposition of double blind intranasal study drug

•

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asthma, with the exception of mild intermittent asthma [NAEPP, 2007; GINA, 2006], or very mild asthma (Canada) [Lemiére, 2004].

NOTE: Subjects will be allowed to use short-acting inhaled beta2 agonists ONLY on an as needed basis.

2.

3.

•

rhinitis medicamentosa

•

bacterial or viral infection (e.g., common cold) of the eyes or upper respiratory tract within two weeks of Visit 1 or during the screening period

•

documented evidence of acute or significant chronic sinusitis, as determined by the individual investigator

•

current or history of glaucoma and/or ocular herpes simplex

•

current cataract

•

physical impairment that would affect subject’s ability to participate safely and fully in the study

•

clinical evidence of a Candida infection of the nose

•

history of psychiatric disease, intellectual deficiency, poor motivation, substance abuse (including drug and alcohol) or other conditions that will limit the validity of informed consent or that would confound the interpretation of the study results

•

history of adrenal insufficiency

Use of corticosteroids, defined as: •

Intranasal corticosteroid within 4 weeks prior to Visit 1 (e.g., FLONASE™, VERAMYST, Nasonex, Rhinocort).

•

Inhaled, oral, intramuscular, intravenous, ocular, and/or dermatological corticosteroid (with the exception of hydrocortisone cream/ointment, 1% or less, or equivalent) within 8 weeks prior to Visit 1.

Use of other allergy medications within the timeframe indicated relative to Visit 1 •

Intranasal or ocular cromolyn within 14 days prior to Visit 1 (e.g., Nasalcrom, Crolom)

•

Short-acting prescription and non-prescription antihistamines, including ocular preparations and antihistamines contained in insomnia and “night time” pain formulations, within 3 days prior to Visit 1 (e.g., Benadryl, Chlortrimeton, Dimetane, Tavist)

•

Long-acting antihistamines within 10 days prior to Visit 1, including loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, terfenadine (e.g., Allegra, Claritin, Clarinex, Zyrtec)

•

Long-acting antihistamine, astemizole, within 12 weeks prior to Visit 1

•

Intranasal antihistamines (e.g., Astelin) within 2 weeks prior to Visit 1

•

Oral or intranasal decongestants within 3 days prior to Visit 1 (e.g., Sudafed) - 21 -

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•

Long-acting beta-agonists within 3 days prior to Visit 1 (e.g., SEREVENT™, Foradil)

•

Intranasal, oral, or inhaled anticholinergics within 3 days prior to Visit 1 (e.g., Atrovent)

•

Histamine H2-receptor antagonists including cimetidine, ranitidine, famotidine, nizatidine (e.g., ZANTAC™, Tagamet, Pepcid, Axid) within 1 day prior to Visit 1

•

Oral antileukotrienes within 3 days of Visit 1 (e.g., Singulair)

•

Subcutaneous omalizumab (Xolair) within 5 months of Visit 1

•

Subjects are not permitted to use any artificial tears, eyewashes/nasal irrigation solutions, homeopathic preparations, lubricants, sympathomimetic or vasoconstrictor preparations during the screening and treatment periods. No exclusion period prior to screening (Visit 1) is required for these treatments.

Use of other medications that may affect allergic rhinitis or its symptoms •

Chronic use of concomitant medications, such as tricyclic antidepressants, that would affect assessment of the effectiveness of the study drug

•

Use of other intranasally administered medications (e.g., Miacalcin)

5.

Use of immunosuppressive medications eight weeks prior to screening and during the study

6.

Immunotherapy Immunotherapy patients may be enrolled in the study as long as the immunotherapy was not initiated within 30 days of Visit 1 and if the dose has remained fixed over the 30 days prior to Visit 1, and the dose will remain fixed for the duration of the study.

7.

Use of any medications that significantly alter the pharmacokinetics of fluticasone furoate, including ritonavir and ketoconazole

8.

Allergy/Intolerance •

9.

Known hypersensitivity to corticosteroids, or any excipients in the product

Use of contact lenses

10. Use of Nasal Continuous Positive Airway Pressure (C-PAP) device (mask or pillow) 11. Clinical trial/experimental medication experience •

Participation in a clinical trial within 12 months prior to Visit 1

•

Participation in a previous or current FFNS (GW685698X) clinical study

12. Positive pregnancy test or female who is breastfeeding •

Has a positive or inconclusive pregnancy test at Visit 1 or Visit 2

13. Affiliation with investigational site

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Subject is a participating investigator, sub-investigator, study co-ordinator, or employee of a participating investigator, or is an immediate family member of the aforementioned.

14. Current tobacco use •

Subject currently uses, or has used within the past year, smoking products including cigarettes, cigars, and pipe or chewing tobacco.

15. Chickenpox or measles •

A subject is not eligible if he/she currently has chickenpox or measles, or has been exposed to chickenpox or measles during the last three weeks and is nonimmune. If a subject develops chickenpox or measles during the study, he/she will be withdrawn from the study. If a non-immune subject is exposed to chickenpox or measles during the study, his/her continuation in the study will be at the discretion of the investigator, taking into consideration the likelihood of developing active disease.

16. Findings of a clinically significant, abnormal electrocardiogram (ECG) 17. Findings of a clinically significant laboratory abnormality

4.5.

Screen Failures

A subject who is assigned a subject number, has signed the informed consent, and completed at least one study procedure, but is not randomized to study treatment drug, has failed screening. The following information will be collected on subjects who fail screening: •

demographic information including race, age, and gender,

•

subject recruitment information

•

reason for screen failure (inclusion/exclusion criteria eCRF page, screening failure eCRF page, and randomization criteria eCRF page),

•

SAE information, and

•

Investigator Signature Page

Subjects who do not meet entry criteria may be eligible for re-screening upon consultation with the GSK medical monitor. The subjects will not be eligible for rescreening if he/she did not meet the randomization symptom criteria.

4.6.

Withdrawal Criteria

A subject who takes double-blinded study drug but withdraws prior to Visit 6 has withdrawn early. Subjects who withdraw early will not be replaced. Subject withdrawal from the study is required and Early Withdrawal procedures must be performed, when:

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•

a subject is significantly non-compliant with the requirements of the protocol

•

a subject has not completed the 4-week treatment period

•

a subject becomes pregnant

•

a subject has an adverse event that would, in the investigator’s judgement, make continued participation in the study an unacceptable risk

•

the treatment blind is broken for a subject (by other than GSK GCSP personnel)

•

a subject develops chickenpox or measles

•

a subject meets liver chemistry threshold stopping criteria per Section 6.3.8. or

•

GlaxoSmithKline discontinues the study.

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from participating in this study at any time.

5.

STUDY TREATMENTS

5.1.

Investigational Product and Reference Therapy

All treatments will be supplied by GSK. The treatment label will be a double-blind label. The contents of the labels will be in accordance with all applicable regulatory requirements. Fluticasone Furoate Nasal Spray and Matching Vehicle Placebo Fluticasone furoate nasal spray will be provided as a preserved, aqueous suspension containing 0.05% w/w of micronized fluticasone furoate (see the Investigator’s Brochure and package insert for information on excipients [GlaxoSmithKline Document Number RM2004/00130/02, 2006; VERAMYST Prescribing Information, 2007]). Each nasal spray bottle will contain a volume of suspension sufficient to deliver a minimum of 120 actuations. Each spray of the suspension will contain approximately 27.5mcg of fluticasone furoate. The matching placebo nasal spray is comprised only of the fluticasone furoate vehicle.

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Demonstration devices will be made available to allow site staff to demonstrate proper administration of the nasal sprays. The nasal spray treatments are administered as is from the nasal spray devices, however, each device must be primed before it is used for the first time. This ensures that a full dose will be delivered when the spray is used in the nose. Please refer to the Subject Instruction Leaflet for detailed directions for priming. Storage and Handling Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request. Investigational product must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the investigational product will be limited to the investigator and authorized site staff. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol. The nasal spray treatment should be stored between 15°C and 30°C (59°F and 86°F) in an upright position with the cap on. It should not be refrigerated or frozen. A temperature log of the storage area for the study treatments should be maintained to assure integrity of the treatments. Subjects should be reminded that all study drug supplies must be returned to the study site at each clinic visit, at the completion of the study, or Early Withdrawal. Study site personnel are to reconcile or resolve any discrepancies between the amount of study drug dispensed to subjects, the amount used by the subjects as reported on the treatment ediaries, and the amount returned to the study site. Clinical trial materials must not be loaned or dispensed by the Principal Investigator to another Investigator or site not specified on the Principal Investigator’s Form FDA 1572. At the conclusion of the study, a final inventory will be performed by the study monitor and the Principal Investigator (or designee). If any supplies are unaccounted for, this must be indicated on the drug accountability form together with an explanation of the discrepancy. All used and unused medications together with a copy of the Clinical Supplies Return Form must be returned to GlaxoSmithKline. GlaxoSmithKline personnel will be responsible for packaging and shipping all treatments back to the company in accordance with federal laws. The Principal Investigator must retain copies of the Clinical Supplies Return Form and Drug Accountability records for his/her files.

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Dosing At the entry to the double-blind treatment period (Visit 2), eligible subjects will be assigned to one of the two treatment arms in accordance with the randomization schedule. The first dose of study drug will be self-administered in the clinic prior to noon at Visit 2 to randomized subjects. Subjects will continue to administer study drug each morning for 4 weeks following their pre-dose nasal and ocular symptom assessments and PNIF assessments. Subjects will be educated in the use of the nasal spray using a placebo demonstration device. The nasal spray Subject Instruction Leaflet should be reviewed and provided to the subject to take home with them. Subjects will be instructed to administer two sprays of the nasal spray per nostril taking care to point the end of the nozzle toward the side of the nose, away from the septum. Administration of the dose should be performed by alternately spraying one spray to each nostril followed by a second spray to each nostril.

5.2.

Treatment Assignment

Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. Subjects will be assigned to study treatment at Visit 2, in accordance with a GSK, computer-generated, randomization schedule and an Interactive Voice Response System (IVRS) called the Registration and Medication Ordering System (RAMOS). RAMOS is accessed via a personal identification number (PIN) assigned to each authorized site personnel. Once a subject is eligible for randomization, a unique randomization number and a container number corresponding to a specific medication treatment kit will be assigned to that subject via RAMOS. The medication treatment kit will be dispensed to the subject at this visit. Each subject’s unique randomization number is linked to the specific container number of the medication treatment kit assigned. Once assigned, the kit numbers and randomization numbers cannot be reassigned to any other subject. The randomization number will be documented in the subject’s clinic notes and in the case report form (CRF). Detailed IVRS user instructions and worksheets will be provided at study start-up.

5.3.

Blinding

The 4 week treatment period for this study is double-blind. A copy of the randomization code will be kept in the sponsor and/or designee's file so that all investigators, subjects, and GlaxoSmithKline personnel remain blinded. The investigator or treating physician may unblind a subject’s treatment assignment only in the case of an emergency, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject. Whenever possible, the - 26 -

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investigator must first discuss options with the GSK Medical Monitor or appropriate GSK study personnel before unblinding the subject’s treatment assignment. If this is impractical, the investigator must notify GSK as soon as possible, but without revealing the treatment assignment of the unblinded subject, unless that information is important for the safety of subjects currently in the study. The date and reason for the unblinding must be recorded in the appropriate data collection tool. GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, may be sent to clinical investigators in accordance with local regulations and/or GSK policy. It a subject’s treatment code is unblinded, the subject must be withdrawn from the study.

5.4.

Product Accountability

In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of GSK investigational product dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study. Any nasal sprays that fail to actuate properly must be identified to GSK personnel and returned to GSK for testing. If a subject experiences nasal spray malfunction, the subject should return the nasal spray to the clinic as soon as possible and avoid missing any doses if possible. The site should then call RAMOS and obtain a new treatment nasal spray number for this subject and dispense a new study nasal spray from the site’s investigational product supply as instructed by RAMOS.

5.5.

Treatment Compliance

Subjects will confirm the administration of their daily treatments on the e-diary by answering the question: “Was the nasal spray treatment administered?” During each clinic visit, subjects should be reminded of the importance of administering their daily study treatment. Premature discontinuation of the study drug will be defined as discontinuation of the study drug for more than 2 consecutive days before the end of the study period. Subjects who discontinue administration of study drug prematurely will be withdrawn from the study.

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5.6.

Concomitant Medications and Non-Drug Therapies

5.6.1.

Permitted Medications and Non-Drug Therapies

All concomitant medications taken during the study will be recorded in the eCRF. The minimum requirement is that drug name and the dates of administration are to be recorded. No other anti-allergy or rhinitis medications, including oral, intranasal, ocular treatments, will be permitted during the study. All medications for other disorders may be continued throughout the study, provided the dose remains constant and their use would not be expected to affect the subjects’ nasal or non-nasal symptoms. No corticosteroids are permitted with the exception of topical hydrocortisone (1% or less, or equivalent). Subjects with mild intermittent or very mild asthma may be treated with short-acting inhaled beta2 agonists on an as needed basis ONLY (see Section 4.4). 5.6.2.

Prohibited Medications and Non-Drug Therapies

Concomitant use of any prescription or over-the-counter (OTC) medications that may affect the duration/severity of rhinitis, including oral or intranasal treatments, or non-drug therapies for rhinitis (e.g., Breathe Right nasal strips, humidifiers) will not be allowed during this study. Given below is a specific list of concurrent medications prohibited at any time during the study: •

Intranasal or ocular cromolyn

•

Short-acting prescription or OTC antihistamines, including ocular preparations and antihistamines contained in insomnia and ‘nighttime’ pain formulations taken for insomnia

•

Long-acting antihistamines, including loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, terfenadine

•

Long-acting antihistamine, astemizole, within 12 weeks prior to Visit 1

•

Intranasal antihistamines, including Astelin

•

Corticosteroids: With the exception of topical hydrocortisone (1% or less, or equivalent), subjects must refrain from use of all corticosteroids during the study.

•

Oral or intranasal decongestants

•

Intranasal, oral or inhaled anticholinergics

•

Intranasal medications (other than study treatment)

•

Oral antileukotrienes

•

Long-acting beta-agonists (e.g., salmeterol)

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•

Ophthalmic allergy preparations

•

Ocular antihistamines, eyewashes/irrigation solutions, homeopathic preparations, lubricants, sympathomimetic or vasoconstrictor preparations

•

Use of any medications that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole

•

Subcutaneous omalizumab (Xolair)

•

Chronic use of tricyclic antidepressants or other concomitant medications that would affect assessment of the effectiveness of the study medication

•

Immunosuppressive medications (e.g., cyclophosphamide)

•

Nasal Continuous Positive Airway Pressure (C-PAP) device (mask or pillow)

•

Immunotherapy patients may be enrolled into the study if the immunotherapy was not initiated within 30 days of Visit 1, the dose has remained fixed over the 30 days prior to Visit 1, and the dose will remain fixed for the duration of the study.

5.7.

Treatment after the End of the Study

There is no extension study associated with this protocol. No post-study treatment will be provided.

5.8.

Treatment of Investigational Product Overdose

An overdose is defined as a dose greater than the total doses described above which results in clinical signs or symptoms. In the event of an overdose of study medication, the investigator should use clinical judgement in treating the overdose and contact the study medical monitor. The Investigator’s Brochure for GW685698X and VERAMYST Prescribing Information should be referenced for any safety concerns [GlaxoSmithKline Document Number RM2004/00130/02, 2006; VERAMYST Prescribing Information, 2007].

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STUDY ASSESSMENTS AND PROCEDURES

Table 1 includes the Time and Events for this study: Table 1

Time and Events Table Visit Number 1

2

3

4

5

6

EWa Phone Callb

Time Relative to Visit (Day) -14 to -7

1

Permitted Visit Window

8 ±3

15 ±3

22 ±3

29 ±3

32 +2

Time Relative to Visit (Week) -2 to -1

0

1

2

3

4

5

ACTIVITY Informed consent

X

PGx Informed consent Xc Subject number assignment X Medical history/disease history/Demographics X Concomitant medication assessment X X X X X X X Verification of inclusion/exclusion criteria X X Vital Signs and Physical Examination X X X Nasal examination X X X X X X X Skin testing (prick method) if not done within 12 months X of Visit 1 Clinical laboratory tests (hematology and chemistry) X X X 12-lead ECGs X Issue electronic diary and review use for screening X period Dispense PNIF meter and face mask, review instructions, X and demonstrate proper use Adverse event assessment X X X X X X X Urine pregnancy test (all females of childbearing X X X X X potential) Randomization number assignment X RQLQ(S)d X X X Review use of electronic diary for treatment period X Nasal spray technique demonstration X Dispense double-blind study drug to eligible subjects X Pharmacogenetic sampling X X Collect double-blind study drug X X Collect electronic diary, PNIF meter and face mask X X Compliance assessment X X X X X X a. Early Withdrawal b. Follow-up telephone call to subject must be made within 3-5 days following Visit 6 or Early Withdrawal. c. The PGx informed consent may be obtained anytime during the study but prior to taking the PGx blood sample. d. The RQLQ(S) should be completed at the beginning of the visit.

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Critical Baseline Assessments

Subjects must complete baseline nasal and ocular symptom assessments, PNIF assessments, and meet inclusion/exclusion criteria in order to be eligible for randomization.

6.2.

Efficacy

All efficacy measures for nasal (rhinorrhea, nasal congestion, nasal itching, sneezing) symptoms and ocular symptoms (eye itching/ burning, eye tearing/watering, and eye redness) are based on subject-rated, individual symptom assessments as evaluated on a 4 point (0-3) categorical scale, recorded on an e-diary. Efficacy measures for the peak nasal inspiratory flow (PNIF) are also based on the subject twice-daily assessments using an In-Check portable hand-held nasal inspiratory flow meter and face mask (Clement-Clarke International, Harlow, UK), recorded on the e-diary. 6.2.1. •

Primary Efficacy Endpoint

Mean change from baseline over the entire treatment period in daily, reflective, total nasal symptom scores (rTNSS) The TNSS is equal to the sum of the four individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing.

6.2.2.

Secondary Efficacy Endpoints

6.2.2.1.

Key Secondary Endpoints

•

Mean change from baseline over the entire treatment period in morning (AM), predose, instantaneous total nasal symptom scores (iTNSS) The AM, pre-dose, iTNSS is the sum of the 4 individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing performed at the moment immediately prior to taking their dose

•

Mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS) The TOSS is equal to the sum of the three individual ocular symptom scores for eye itching/burning, eye tearing/watering, and eye redness.

6.2.2.2.

Other Secondary Endpoints

Total Nasal Symptoms

•

Mean change from baseline over the entire treatment period in AM rTNSS

•

Mean change from baseline over the entire treatment period in PM rTNSS

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•

Mean percent change from baseline over the entire treatment period in daily rTNSS

•

Mean percent change from baseline over the entire treatment period in AM, predose iTNSS

Individual Nasal Symptoms

•

Mean change from baseline over the entire treatment period in individual, daily, reflective, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

•

Mean change from baseline over the entire treatment period in individual AM, pre-dose, instantaneous, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

•

Mean change from baseline over the entire treatment period in individual, AM, reflective, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

•

Mean change from baseline over the entire treatment period in individual, PM, reflective, nasal symptom scores for rhinorrhea, nasal congestion, nasal itching and sneezing

Total Ocular Symptoms

•

Mean change from baseline over the entire treatment period in AM, pre-dose, instantaneous, total ocular symptom scores (iTOSS)

•

Mean change from baseline over the entire treatment period in AM rTOSS

•

Mean change from baseline over the entire treatment period in PM rTOSS

•

Mean percent change from baseline over the entire treatment period in daily rTOSS

•

Mean percent change from baseline over the entire treatment period in AM, pre-dose iTOSS

Individual Ocular Symptoms

•

Mean change from baseline over the entire treatment period in individual, daily, reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, and eye redness

•

Mean change from baseline over the entire treatment period in individual AM, pre-dose, instantaneous, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness

•

Mean change from baseline over the entire treatment period in individual AM, reflective, ocular symptom scores for eyesitching/ burning, eye tearing/watering, eye redness

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Mean change from baseline over the entire treatment period in individual PM reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness

Peak Nasal Inspiratory Flow (PNIF)

•

Mean change from baseline over the entire treatment period in daily peak nasal inspiratory flow (PNIF)

•

Mean change from baseline over the entire treatment period in AM peak nasal inspiratory flow

•

Mean change from baseline over the entire treatment period in PM peak nasal inspiratory flow

The PNIF is an objective measure of nasal airflow obstruction. 6.2.3.

Assessments Recorded on Electronic Diaries

In order to evaluate efficacy, subjects will be provided with e-diaries on which to record the severity of their allergy symptoms. Subjects will record information on the e-diaries for the following time periods: •

Subjects will record the severity of their nasal and ocular symptoms on the e-diary during the screening phase (from Visit 1 to Visit 2) to capture the subjects’ baseline symptom scores.

•

A treatment e-diary will be used beginning on the day of Visit 2 (first day of study treatment administration) and throughout the remainder of the study.

Subjects will also document PNIF measurements and study drug compliance on the ediary. Any medical problems (other than allergic rhinitis) and medications used will also be documented by the subjects. Rating

Subjects will use the following 0 to 3 scale to assess the severity of each of the symptoms assessed in the study: 0 = none (symptom is not present) 1 = mild (sign/symptom is clearly present but minimal awareness; easily tolerated) 2 = moderate (definite awareness of sign/symptom that is bothersome but tolerable) 3 = severe (sign/symptom is hard to tolerate; causes interference with activities of daily living and/or sleeping) Rating Period

Using the 0 to 3 scale above, subjects will be instructed to score and document their symptoms in a reflective manner and an instantaneous manner on an electronic diary.

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•

The reflective rating represents the subject’s symptoms over the preceding 12 hours. This assessment provides information on how effective the treatment is throughout the day and will be performed TWICE daily (AM and PM). The AM assessment must be performed prior to administering the morning dose and assesses how the subject felt through the night. The PM reflective rating must be done approximately 12 hours after dosing but before bedtime and assesses how the subject felt during the day.

•

The instantaneous rating represents the subject’s symptoms at the time of the assessment or at that “instant”. The instantaneous rating will be performed ONCE daily, in the morning, and will be made prior to administering their morning dose. This assessment will provide information on the efficacy of the treatment at the end of the 24-hour dosing interval.

At Visit 1 (screening), subjects will be given the e-diary to rate the severity of their nasal and ocular symptoms in the morning (AM rTNSS, AM rTOSS, pre-dose iTNSS, pre-dose iTOSS) and in the evening (PM rTNSS, PM rTOSS) every day as instructed above. At Visit 2, the e-diary will be reviewed with the subject to determine eligibility for randomization. The clinician will calculate/confirm each subject’s daily rTNSS and rTOSS in order to determine eligibility. To be eligible for randomization, the subjects must meet the randomization criteria as outlined in Section 4.3. Randomized subjects will be instructed on how to complete the daily e-diaries during the treatment period. The e-diaries will be reviewed with the subject by the clinician or designee at Visits 2, 3, 4 and 5. The e-diary will be reviewed and collected at Visit 6 (or at Early Withdrawal). Assessment Compliance

At each clinic visit, subjects will be reminded to complete their twice-daily symptom and PNIF assessments on the e-diaries. 6.2.4.

Nasal Symptoms

The primary and secondary nasal endpoints used to evaluate efficacy will be calculated from the subject-rated nasal symptom scores of the four nasal symptoms of rhinorrhea, nasal congestion, itching, and sneezing. Subjects will use the 0 to 3 scale described in Section 6.2.3. to assess these symptoms. 6.2.5.

Ocular Symptoms

The ocular endpoints used to evaluate efficacy will be calculated from the subject-rated, ocular symptom scores of the three ocular symptoms of itching/burning, tearing/watering, and redness. Subjects will use the 0 to 3 scale described in Section 6.2.3. to assess these symptoms.

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Peak Nasal Inspiratory Flow (PNIF)

Peak nasal inspiratory flow (PNIF) will be measured by subjects using an In-Check Nasal portable hand-held inspiratory flow meter and face mask (Clement-Clarke International, Harlow, UK). For baseline PNIF measurement, the last 8 readings (4 AM assessments and 4 PM assessments) over the four 24-hour periods prior to randomization will be averaged. Subjects will measure PNIF twice daily (once in the AM prior to taking their study medication, and again in the PM). PNIF measurements should be completed and recorded by the subject following assessment of nasal and ocular symptoms in the AM (prior to taking their study medication), and 12 hours later in the PM (after they record their nasal and ocular symptoms on the e-diaries). Three measurements will be taken on each occasion and the highest measurement recorded on the e-diary. Subjects will be instructed on how to properly use the PNIF meter and face mask during the screening visit (Visit 1).

6.3.

Safety

6.3.1.

Safety Endpoints

Safety endpoints for the study are: •

Frequency and type of clinical adverse events

•

Clinical laboratory tests (hematology and chemistry)

•

Nasal examinations (mucosal bleeding, ulcers, polyps, and fungal infections)

•

Vital signs (systolic and diastolic blood pressure, heart rate [pulse])

6.3.2.

Medical History and Concomitant Drug Use

The portion of the subject’s medical history that relates to concurrent diseases, concomitant medication use (including drugs discontinued at screening), and drug allergies will be recorded in the subject record at Visit 1. Any new information obtained after Visit 1 regarding these aspects of their medical history will be added to the subject record at the time of the contact. Subjects will document any medical conditions experienced and any concomitant medications taken during the study. All concomitant medications taken during the study will be recorded in the eCRF. The minimum information required to be recorded is the drug name and the dates of administration. 6.3.3.

Physical Examination

A physical examination will be conducted at Visit 1 (Screening) and Visit 6/Early Withdrawal by the investigator, nurse practitioner, or physician’s assistant listed on the FDA Form 1572. Physical examination results will be documented in the source documents only. Any unfavourable changes from the Visit 1 assessment will be recorded as an adverse event, documenting the start and stop dates of the adverse event.

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Nasal Examination

A nasal examination will be performed by the investigator at all visits (Visits 1 – 6 or Early Withdrawal) and the findings recorded on the nasal examination eCRF page. Assessments will be done for mucosal bleeding, ulcers, polyps, and fungal infections. Any unfavorable changes that are not reflective of the symptoms of allergic rhinitis from the Visit 1 assessment will be recorded as an adverse event, documenting the start and stop dates of the adverse event. Every effort should be made to assure the same practitioner performs the nasal examinations for a given subject at all visits for consistency. Should the investigator recognize symptoms of a nasal fungal infection, a fungal culture should be performed. Culture kits will be provided for testing through the central laboratory. A diagnosis of nasal candidiasis should be reported as an adverse event. 6.3.5.

Vital Signs

Vital signs (heart rate [pulse], systolic and diastolic blood pressure) will be measured at Visit 1 and Visit 6/Early Withdrawal with the subject in the seated position. The subject must be seated at least five minutes before these measurements are done. A single set of values for heart rate [pulse] and blood pressure (systolic and diastolic) will be determined and recorded in the eCRF. The subject’s height and weight will also be recorded in the eCRF at Visit 1. 6.3.6.

Clinical Laboratory Tests

Routine laboratory tests (see Appendix 2: Clinical Laboratory Assessments) will be performed at Visit 1 and Visit 6/Early Withdrawal visit. Subjects will not be required to fast prior to collection of the laboratory specimens. Quest Diagnostics, a central laboratory, will provide a manual to each site containing detailed instructions for collecting all specimens. Results of the laboratory tests will be transmitted electronically to GSK. A printout from the central laboratory of the results will be maintained at the site and will be signed and dated by the investigator confirming review. In cases of emergency when another laboratory other than the central lab is utilized, the investigator will supply GSK with the name, address of the laboratory, a copy of the certification, certification number, date of certification, and a list of normal values for all laboratory tests required by the protocol. Updated versions of these documents must be provided to GSK as appropriate. GSK will provide the above documentation for the central laboratory for this study, Quest Diagnostics, to the Principal Investigator. The investigator must assess the results of all clinical laboratory tests to determine each subject’s eligibility to continue in the study. Any subject with all analytes within their respective reference range is eligible to continue. For any subject who has an analyte outside the reference range, the investigator has three options:

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1.

Exclude the subject from the study due to the deviant result and/or the uncertain clinical significance of the deviant result.

2.

Repeat, at the earliest opportunity, the test for the analyte on a new specimen to assess the possibility of laboratory error.

3.

Document the subject’s eligibility for the study on the basis of one of the following explanations for the deviant result: •

Abnormality due to concurrent illness, disease process, or condition that would not render the subject in question at higher risk than a subject without a similar deviation in laboratory tests (e.g., eosinophilia in atopic subjects).

•

Normal deviation for age (e.g., elevated alkaline phosphatase).

•

Clinically insignificant deviation from normal values (i.e., in the judgement of the physician/investigator, the deviation does not indicate the presence of a disease state or compromised, predisposing state which renders the subject in question at higher risk than a subject without a similar deviation in laboratory tests).

Abnormal laboratory values resulting in an adverse event or serious adverse event (e.g., hospitalization) must be reported to GSK as an adverse event or serious adverse event as outlined in Section 6.3.7.1 and Section 6.3.7.2, respectively, of this protocol. Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal assessments (e.g., abnormal ECGs, vital signs, etc.) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 6.3.7.1 ("Definition of an AE"), or SAE, as defined in Section 6.3.7.2 ("Definition of a SAE"). Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject’s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs. The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant. 6.3.7.

Adverse Events

The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

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Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 6.3.7.2.

Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose: a.

Results in death

b.

Is life-threatening NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c.

Requires hospitalization or prolongation of existing hospitalization NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d.

Results in disability/incapacity, or NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e.

Is a congenital anomaly/birth defect

f.

Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive - 38 -

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treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. 6.3.8.

Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition, are not to be reported as AEs or SAEs. Liver Chemistry Threshold for Discontinuation In the phase 3 clinical development program, FFNS was not associated with any AEs suggestive of liver injury. However, in the event a liver function abnormality should occur, an assessment of the liver should be performed as described in this section. Liver chemistry threshold stopping criteria have been designed to assure subject safety. Complete the liver event case report forms if protocol-specified liver chemistry subject stopping criteria are met. Complete the liver imaging and/or liver biopsy case report forms if these tests are performed. When subjects meet the following liver chemistry threshold criteria, investigational product must be permanently withdrawn, additional testing performed, and the subject monitored until liver chemistries resolve, stabilize, or return to baseline values. The subject must then be permanently withdrawn from the study: •

ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (>35% direct).

•

ALT ≥ 5xULN.

•

ALT ≥ 3xULN if associated with the appearance or worsening of hepatitis symptoms or rash.

Subjects with ALT ≥3xULN and <5xULN and bilirubin <1.5xULN, who do not exhibit hepatitis symptoms or rash, can continue investigational product and be monitored weekly for up to 4 weeks. At any point, if these subjects meet the liver chemistry threshold stopping criteria (outlined above) or are unable to return for weekly liver chemistries, investigational product must be permanently stopped, additional testing performed, and the subject continue safety followup until liver chemistries resolve, stabilize, or return to baseline values. The subject must then be withdrawn from the study.

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Subjects with ALT ≥3xULN and bilirubin ≥1.5xULN (>35% direct bilirubin; bilirubin fractionation required) must be immediately and permanently withdrawn from investigational product. Every attempt must be made to have the subject return to clinic (within 24 hours) for repeat liver chemistries and additional testing, and monitored closely (with specialist or hepatology consultation recommended). This event must be reported to GSK within 24 hours of learning of its occurrence. Subjects must be monitored twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values. Upon completion of the safety follow-up, the subject must then be withdrawn from the study. Subjects with ALT ≥5xULN or ALT ≥3xULN with hepatitis or rash or if increase persists ≥4 weeks must be immediately withdrawn from investigational product. Every attempt must be made to have the subject return to clinic within 24-72 hrs for repeat liver chemistries and additional testing, and monitored weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values. This event must be reported to GSK within 24 hours of learning of its occurrence. Subjects with ALT ≥3xULN and <5xULN and bilirubin <1.5xULN can continue investigational product, with every attempt made to have the subject return for repeat liver chemistries within one week, and be monitored weekly for up to 4 weeks. However, subjects unable to be monitored for 4 weeks must be withdrawn from investigational product and monitored weekly until liver chemistries resolve, stabilize or return to within baseline values. These subjects must be withdrawn from the study. This event must be reported to GSK within 24 hours of learning of its occurrence. If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <1.5xULN, subjects should be monitored twice monthly until liver chemistries normalize or return to within baseline values. Note that investigational product must be withdrawn if bilirubin >1.5xULN or there are signs/symptoms of hepatitis or hypersensitivity or elevations in ALT ≥3xULN and <5xULN persist for more than 4 weeks. In all the above situations, every attempt must be made to obtain the following: •

Viral hepatitis serology including: •

Hepatitis A IgM antibody;

•

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);

•

Hepatitis C RNA;

•

Cytomegalovirus IgM antibody;

•

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);

•

Hepatitis E IgM antibody (if subject resides outside the USA or Canada, or has traveled outside USA or Canada in past 3 months)

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•

Blood sample for pharmacokinetic (PK) analysis, obtained within 3 half-lives of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF.

•

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

•

If bilirubin>1.5xULN, fractionate bilirubin.

•

Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, putative hepatotoxins, or alcohol on the concomitant medications report form.

The following are required for subjects with ALT ≥3xULN and bilirubin ≥1.5xULN but are optional for other abnormal liver chemistries: •

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies.

•

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

6.3.9.

Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs

There are no disease-related events and/or disease-related outcomes not qualifying as SAEs for this study. 6.3.10.

Time Period and Frequency of Detecting AEs and SAEs

Adverse Events

All AEs will be collected from Visit 1 through Visit 6 or Early Withdrawal. At every visit, after the subject has had an opportunity to spontaneously mention any problems, the Investigator should inquire about AEs by asking the following standard questions: • “Have you had any (other) medical problems or worsening of any medical problems since your last visit/assessment?” •

“Have you taken any new medicines, other than those given to you in this study, since your last visit/assessment?”

Subject diary information will be reviewed at each visit and if the subject does not mention an event that is recorded, he/she should be questioned for further information in order to determine if there was some occurrence of an adverse event. If an AE is unresolved at the time of the last visit, refer to the Study Procedures Manual for followup requirements.

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Serious Adverse Events

From the time a subject consents to participate in and completes the study (including any follow-up period), all SAEs assessed as related to study participation (e.g., protocolmandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be reported promptly to GSK. 6.3.11.

Pregnancy

There is insufficient information regarding the use of corticosteroids during pregnancy and lactation to properly assess their effects. Confirmation of pregnancy at Visit 1 or Visit 2 is an exclusion criterion for this protocol. Inconclusive pregnancy results would also exclude the subject from the study. Pregnancy Testing

Pregnancy testing for females of childbearing potential will be performed as specified in Section 6, Table 1. A urine pregnancy test will be performed at Visits 1, 2, 5, 6/EW for all females of childbearing potential. Pregnancy Reporting

Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications, and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the investigational product, must be promptly reported to GSK. 6.3.12.

Medical Devices

No GSK medical devices are involved in this study. GSK will provide the In-Check Nasal portable hand-held inspiratory flow meters and face masks (Clement-Clarke International, Harlow, UK) for use in the study. Instructions for use and care of these devices will be provided in the SPM.

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Prompt Reporting of Serious Adverse Events and Other Events to GSK

SAEs, pregnancies, medical device incidents and near-incidents, and liver function abnormalities meeting pre-defined criteria will be reported promptly to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event. Initial Reports Type of Event All SAEs

Time Frame 24 hours

Pregnancy

2 Weeks

Liver chemistry abnormalities: ALT≥3xULN PLUS Bilirubin≥1.5xULN) ALT≥5xULN or ALT≥3xULN with hepatitis or rash or ≥4 weeks ALT≥3xULN and <5xULN and biliribin <1.5xULN

Documents “SAE” data collection tool Pregnancy Form

Follow-up Information on a Previous Report Time Frame Documents 24 hours Updated “SAE” data collection tool 2 Weeks Updated Pregnancy Form

24 hours

Liver Chemistry Report Form

24 hours

24 hours

Liver Chemistry Report Form

24 hours

24 hours

Liver Chemistry Report Form

24 hours

Updated Liver Chemistry Report Form Updated Liver Chemistry Report Form Updated Liver Chemistry Report Form

The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in the SPM. Procedures for post-study AEs/SAEs are provided in the SPM.

6.4.

Health Outcomes

6.4.1.

Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ (S)]

The Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [(RQLQ(S) [Juniper, 1999] is a 28-item, self-administered, disease-specific (allergic rhinitis), quality of life instrument, which assesses quality of life over a one-week interval. Each question is scored from 0 to 6, with higher scores indicating more impairment on quality of life. Items are grouped into seven domains: Activity limitations (3 items), which allows subjects to rate three standardized activities, Sleep problems (3 items), Non-nose/eye symptoms (7 items), Practical problems (3 items), Nasal symptoms (4 items), Eye symptoms (4 items) and Emotional function (4 items). An overall quality of life score can be calculated from the mean score of all items. - 43 -

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At Visit 2, the subject should complete the first RQLQ(S) prior to randomization. Subjects will complete the RQLQ(S) again at Visit 6/Early Withdrawal. 6.4.1.1.

Questionnaire administration guidelines

To avoid biasing responses, subjects should not be told the results of diagnostic tests prior to completing questionnaires. Self-administered questionnaires must be completed by the subject according to the schedule detailed in Section 6, Table 1. The subject should be requested to complete the questionnaires as completely and as accurately as possible. The RQLQ(S) should be completed at the beginning of the visit, prior to the medical history and adverse event standard questions (“Have you had any (other) medical problems since your last visit?” and “Have you taken any new medicines (other than those given to you in this study), since your last study visit/assessment?”). The subject should be given adequate time to complete all items. No stated or implied time limit for completing the questionnaires will be given. If the subject should request help or clarification of any question in the questionnaire, the study personnel is/are to instruct the subject to reread the instructions and to give the best answer possible to each question. The study personnel will not provide the subject with an answer to any question. After the subject has completed the questionnaire, the investigator or his designee will review the questionnaire for completeness. If the questionnaire (or any portion of it) is incomplete, the subject will be given the opportunity to complete any missing items prior to conclusion of the study visit. The investigator is under no obligation to review or to validate the accuracy of the study completed questionnaires. It is necessary, however, for the study personnel and the clinical research monitor to check the accuracy of subject identification on the questionnaire. Subjects must use a pen to complete the questionnaires. If the subject wishes to change a response, the original response should be crossed out with a single line and the alternative response should be marked. Once the subject returns the questionnaire to the investigator or study personnel, no changes will be allowed. If the subject fails to return to the clinic for subsequent study visits, the investigator or his designee will contact the subject and request that the subject reschedule the visit as soon as possible. If the subject withdraws or is terminated from the study, the investigator will request the subject complete the RQLQ(S) questionnaire at the Early Withdrawal Visit. 6.4.1.2.

Health outcome source documents

Information collected on the eCRF and the health outcome questionnaires are independent components of the study. No attempt will be made to reconcile data recorded on the health outcome questionnaires with data recorded in the clinical eCRF, except for the demographic information (e.g., subject number, gender, investigator number, etc.).

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Upon each subject’s completion of the study, the investigator’s signature on the Investigator’s Signature eCRF page signifies that each subject has been given the opportunity to complete the health outcome questionnaires as described previously. The investigator and the clinical research monitor will not confirm the accuracy or the completeness of the health outcome questionnaire responses.

6.5.

Pharmacogenetics

Information regarding pharmacogenetic research is included in Appendix 1: PGx. The IEC/IRB and, where required, the applicable regulatory agency must approve the PGx assessments before these can be conducted at the site. The approval(s) must be in writing and will clearly specify approval of the PGx assessments (i.e., approval of Appendix 1: PGx). In some cases, approval of the PGx assessments can occur after approval is obtained for the rest of the study. If so, then the written approval will clearly indicate approval of the PGx assessments is being deferred and in most cases, the study, except for PGx assessments, can be initiated. When PGx assessments will not be approved, then the approval for the rest of the study will clearly indicate this and therefore, PGx assessments will not be conducted.

7.

DATA MANAGEMENT

Data Management will identify and implement the most effective data acquisition and management strategy for each clinical trial protocol and deliver datasets which support the protocol objectives. For this study, subject data will be entered into GSK defined electronic case report forms (eCRFs), transmitted electronically to GSK and combined with data provided from other sources (eg diary data, laboratory data) in a validated data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures with the objective of removing errors and inconsistencies in the data which would otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical Study Report. Adverse events and concomitant medications terms will be coded using MedDRA and GSKDrug, an internal validated medication dictionary. In all cases, subject initials will not be collected nor transmitted to GSK.

8.

DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

8.1.

Hypotheses

The purpose of this study is to compare the efficacy and safety of FFNS 110mcg QD aqueous nasal spray with vehicle placebo nasal spray. The hypothesis that corresponds to the primary and secondary analyses is H0: µ110 = µPBO - 45 -

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HA: µ110 ≠ µPBO where µ110 and µPBO represent the mean changes (or percent change) from baseline over the entire treatment period on efficacy measures for FFNS nasal spray 110mcg QD and vehicle placebo treatment groups, respectively.

8.2.

Study Design Considerations

8.2.1.

Sample Size Assumptions

The study randomization is planned for equal allocation of subjects among two treatment groups. A total of 288 subjects are required for this study, with 144 subjects in each of the two treatment groups: FFNS 110mcg QD aqueous nasal spray and vehicle placebo. The randomization will be stratified by country to account for possible country effects on the study outcome due to country-specific medical practices. 8.2.2.

Sample Size Sensitivity

The standard deviation for the mean change from baseline over the entire treatment period is assumed to be 2.6, based on previous GSK allergy rhinitis studies. The proposed sample size should provide 90% power to detect a difference of 1.0 between active treatment and placebo in mean change from baseline over the entire treatment period in daily rTNSS, using a two-sample t-test with a 0.05 two-sided significance level. To demonstrate the sensitivity of the sample size calculation for this study, Table 2 presents the power of the study under different circumstances in terms of the standard deviation and the observed treatment difference in mean change from baseline over the entire treatment period in rTNSS (assumption used is shaded). Table 2

Power calculations

Standard Deviation 2.2 2.4 2.6 2.8 3.0 8.2.3.

True Treatment Difference between FFNS and Placebo 0.7 0.8 0.9 1.0 1.1 1.2 77% 86% 93% 97% 98% 99% 70% 80% 88% 94% 97% 98% 63% 73% 83% 90% 94% 97% 56% 67% 77% 85% 91% 95% 51% 61% 71% 80% 87% 92%

Sample Size Re-estimation

Sample size re-estimation is not planned.

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Data Analysis Considerations

8.3.1.

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The efficacy, safety, and health outcomes analyses will use the Intent-to-Treat (ITT) population. The ITT population is defined as all randomized subjects who receive at least one dose of study drug. 8.3.2.

Analysis Data Sets

The diary data will comprise the primary data set of interest and Days 1-28 (i.e. the average of all on-treatment data during the four-week treatment period) is the primary time point of interest. 8.3.3.

Treatment Comparisons

All efficacy measures for nasal symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), and ocular symptoms (eye itching/ burning, eye tearing/watering, eye redness) are based on subject-rated, individual symptom assessments, as evaluated on a 4 point (0 to 3) categorical scale, recorded on the electronic diary. Efficacy measures for the peak nasal inspiratory flow (PNIF) are also based on the subject’s twice daily assessments using an In-Check Nasal portable hand-held inspiratory flow meter and face mask (Clement-Clarke International, Harlow, UK), recorded on the electronic diary. 8.3.3.1.

Primary Comparisons of Interest

The primary efficacy endpoint will be the mean change from baseline over the entire treatment period in daily reflective total nasal symptom scores (daily rTNSS). The primary comparison will be made on the primary efficacy measure between FFNS 110mcg QD and vehicle placebo. The total nasal symptom score (TNSS) is defined as the sum of the following four individual nasal symptom scores: rhinorrhea, nasal congestion, nasal itching and sneezing. Each of these 4 nasal symptoms will be evaluated by the subject using a 4 point (0 to 3) categorical scale and recorded on the electronic diary. The rTNSS is a rating of the severity of symptoms over the previous 12 hours and is performed in the morning (AM) and evening (PM). Daily (i.e., during one dosing interval) rTNSS is defined as the average of the PM rTNSS and the AM rTNSS of the next day prior to AM dosing. For example, the Day 1 rTNSS will be computed as: [(PM rTNSS)Day 1, first day of dosing + (AM rTNSS)Day 2, prior to second dosing]/2, and the Day 28 rTNSS will be computed as: [(PM rTNSS)Day 28, last day of dosing + (AM rTNSS)Day 29, last clinic visit]/2. The baseline daily rTNSS is defined as the as the average of the daily rTNSS over the 4 consecutive 24-hour periods prior to randomization, including the assessment the morning of randomization. Change from baseline over the entire treatment period in daily rTNSS will be calculated

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for each subject as the average of the non-missing daily rTNSS during the treatment period minus the baseline daily rTNSS. 8.3.3.2.

Other Comparisons of Interest

The key secondary efficacy endpoints include: •

Mean change from baseline over the entire treatment period in AM pre-dose instantaneous TNSS (iTNSS), where AM pre-dose iTNSS is the sum of the 4 individual nasal symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing performed immediately prior to dosing

•

Mean change from baseline over the entire treatment period in daily, reflective, total ocular symptom scores (rTOSS)

The total ocular symptom score (TOSS) is the sum of the 3 individual ocular symptom score assessments of itching/burning eyes, tearing/watering eyes, and eye redness (scored using a 4 point [0 to 3] categorical scale). The daily reflective and AM, pre-dose instantaneous TOSS will be calculated in the same manner as for TNSS. Other secondary efficacy endpoints include: •

•

•

Total Nasal Symptoms: •

Mean change from baseline over the entire treatment period in AM rTNSS

•

Mean change from baseline over the entire treatment period in PM rTNSS

•

Mean percent change from baseline over the entire treatment period in daily rTNSS

•

Mean percent change from baseline over the entire treatment period in AM, predose iTNSS

Individual Nasal Symptoms: •

Mean change from baseline over the entire treatment period in daily reflective individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline over the entire treatment period in AM pre-dose instantaneous, individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline over the entire treatment period in AM, reflective, individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

•

Mean change from baseline over the entire treatment period in PM, reflective, individual symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing

Total Ocular Symptoms

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•

Mean change from baseline over the entire treatment period in AM, pre-dose, instantaneous, total ocular symptom scores (iTOSS)

•

Mean change from baseline over the entire treatment period in AM rTOSS

•

Mean change from baseline over the entire treatment period in PM rTOSS

•

Mean percent change from baseline over the entire treatment period in daily rTOSS

•

Mean percent change from baseline over the entire treatment period in AM, predose iTOSS

Individual Ocular Symptoms: •

Mean change from baseline over the entire treatment period in individual, daily, reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, and eye redness

•

Mean change from baseline over the entire treatment period in individual AM, pre-dose, instantaneous, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness

•

Mean change from baseline over the entire treatment period in individual AM, reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness

•

Mean change from baseline over the entire treatment period in individual PM reflective, ocular symptom scores for eye itching/ burning, eye tearing/watering, eye redness

Peak Nasal Inspiratory Flow (PNIF): •

Mean change from baseline over the entire treatment period in daily peak nasal inspiratory flow (PNIF)

•

Mean change from baseline over the entire treatment period in AM peak nasal inspiratory flow

•

Mean change from baseline over the entire treatment period in PM peak nasal inspiratory flow

Other efficacy assessments include onset of treatment effect and the time to maximum effect. Safety endpoints will consist of evaluations of clinical adverse events, clinical laboratory tests (hematology and chemistry), nasal examinations, and vital signs. Health outcomes measures will include the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ(S)]. The primary comparison of interest for the RQLQ(S) is the mean change from baseline to endpoint in the global score.

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Multiple Comparisons and Multiplicity

All results from the analyses of the primary efficacy, secondary efficacy, and health outcomes measures will be reported. The primary efficacy endpoint will serve as a gatekeeper for the interpretation of treatment comparisons for the key secondary efficacy and health outcomes endpoints. If H0 is rejected at the 0.05 level for the primary efficacy endpoint, the conclusion will be there is a difference between FFNS 110mcg QD and vehicle placebo, and the p-values for the key secondary efficacy and health outcomes endpoints will be interpreted according to the rules for multiplicity adjustment described below. If H0 is not rejected, the conclusion will be there is no difference between FFNS 110mcg QD and vehicle placebo, and all other p-values will be used for descriptive and exploratory purposes only. To control for multiplicity across the key secondary efficacy endpoints and the health outcomes endpoint (i.e., mean change from baseline to endpoint in the global score of the RQLQ[S]), tests of H0 will be performed in a sequential manner to control the type I error rate at 0.05 as follows: 1.

Mean change from baseline over the entire treatment period in AM, pre-dose iTNSS.

2.

Mean change from baseline over the entire treatment period in daily rTOSS.

3.

Mean change from baseline to endpoint in the RQLQ(S) global score.

No multiplicity adjustments will be made on the other secondary efficacy endpoints. Any p-values ≤0.05 will be identified as nominally significant. 8.3.4.

Interim Analysis

No interim analyses are planned. 8.3.5.

Key Elements of Analysis Plan

For any subject who withdraws from the study early, all available data up to the time of discontinuation of study drug will be included in the Intent-to-Treat population. The number of subjects per site is expected to be approximately 5 - 10 with approximately 40 - 50 investigative sites expected to participate in the study. The analysis model will include country as a covariate. In addition to country, baseline value, age, and gender will be included as covariates in all efficacy analyses, when appropriate. 8.3.5.1.

Derived and Transformed Data

The values for TNSS range from 0 to 12, since each of the four individual nasal symptoms will be scored on a four-point scale from 0 to 3.

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If for a given subject and at a given assessment time (i.e., AM or PM) any of the four symptoms are missing, then the TNSS will be considered missing for that assessment time. If one (but not both) of the AM and PM TNSS is missing for a given day (e.g., a dosing interval during the treatment period), the non-missing TNSS for that day will be used as the TNSS for the day. Missing data on total ocular symptom scores (based on 3 individual symptom scores) will be handled in the same fashion as for the total nasal symptom scores. The total nasal symptom score (TNSS) for each assessment time point is the sum of the 4 individual nasal symptom scores (rhinorrhea, nasal congestion, nasal itching and sneezing. The daily TNSS will be computed as the average of the PM TNSS and the AM TNSS of the next day, based on assessments prior to dosing. For example, the Day 1 TNSS will be computed as: [(PM rTNSS)Day 1, first day of dosing + (AM rTNSS)Day 2, prior to second dosing]/2. The baseline period is defined as 4 days prior to randomization, including the AM symptom assessment on the randomization (i.e., treatment initiation) date. Day 1 assessments include the PM assessment on the randomization (i.e., treatment initiation) date and the AM assessment of the day after treatment initiation. The 28-day treatment period is defined as the first 28 dosing (24-hour) days. Diary data recorded prior to the baseline period or beyond Day 28 of the treatment period will not be used in the efficacy analyses. For both the baseline and treatment periods, a mean TNSS for each subject will be calculated using available diary data from the baseline and treatment periods, respectively, as the average of those non-missing TNSS during the period. The mean change from baseline in (daily, AM, or PM) TNSS will be calculated as the subject's treatment period mean minus the baseline period mean. The total ocular symptom score (TOSS) is the sum of the 3 individual ocular symptom scores (itching/ burning eyes, tearing/watering eyes, eye redness), ranging from 0 to 9. The TOSS for a single day, for the baseline period, and for the treatment period will also be calculated in the same fashion as the total nasal symptom score (TNSS). The peak nasal inspiratory flow (PNIF) for a single day, for the baseline period, and for the treatment period will also be calculated in the same fashion as for nasal and ocular symptom scores. 8.3.5.2.

Efficacy Analyses

In each summary table, sample size, raw mean, median, standard error of the mean, minimum, and maximum will be given. In each analysis table, sample size, least square mean, standard error of the least square mean, least square mean difference, p-values and

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95% confidence intervals (whenever appropriate) for all (unadjusted for multiple comparisons) comparisons will be given. In all analyses described below, the null hypothesis will be a two-sided test of no treatment difference. All statistical tests will use a two-sided significance level of α=0.05. 8.3.5.2.1.

Primary Analysis

The primary efficacy endpoint is the mean change from baseline over the entire treatment period in daily reflective TNSS (rhinorrhea, nasal congestion, nasal itching and sneezing), as evaluated on a 4-point categorical scale. The primary analysis method will be the pairwise comparison of treatment groups (active vs. placebo) using analysis of covariance (ANCOVA) adjusting for baseline rTNSS, country, age, and gender. Mean daily rTNSS will be illustrated over the 28-day treatment period by treatment group. Summary statistics will be displayed for daily rTNSS at baseline, over Week 1, Week 2, Week 3, Week 4, and the entire treatment period. Mean change from baseline in daily rTNSS will be illustrated over time (Day 1 through Day 28) by treatment group. The changes from baseline in daily rTNSS over the entire treatment period will be summarized and analysed. The least squares mean changes for each treatment group will be summarized and compared. The 95% confidence interval (CI) for the treatment mean difference (active & placebo) will also be reported, as well as the p-values corresponding to the test of significance for the treatment mean difference. The changes from baseline in daily rTNSS over Weeks 1, 2, 3, and 4 will also be summarized and analysed. The analysis results of changes over Weeks 1, 2, 3, and 4 will be used to reinforce the robustness of the primary endpoint and will not be adjusted for multiplicity. 8.3.5.2.2.

Secondary Analysis

The secondary efficacy measures on nasal symptoms, ocular symptoms, and peak nasal inspiratory flow will be analysed similarly to the primary analysis. The analysis method will be the pairwise comparison of treatment groups (active vs. placebo) using analysis of covariance (ANCOVA) adjusting for baseline value, country, age, and gender. For each of the secondary efficacy measures outlined in Section 8.3.3.2., the following will be performed: •

Mean change (or mean percent change) from baseline will be illustrated over time (Day 1 to Day 28) for measures of TNSS and TOSS only.

•

Summary statistics will be displayed at baseline, over Week 1, Week 2, Week 3, Week 4, and the entire treatment period.

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Analyses of change from baseline, over Week 1, Week 2, Week 3, Week 4 and the entire treatment period will be performed.

With the exception of the key secondary efficacy measures, the analysis results will be used to support the results for the primary and the key secondary endpoints and will not be adjusted for multiplicity. Time to onset of treatment effect will be assessed by the mean change from baseline in AM pre-dose iTNSS and the mean change from baseline in daily rTNSS (Day 1 to Day 28), and supported by the mean change from baseline in AM rTNSS and PM rTNSS. The time to maximal effect is defined as the earliest day that the mean change from baseline in daily rTNSS demonstrates the greatest reduction as compared to placebo (Days 1-28). 8.3.5.3.

Safety Analyses

Safety data will be summarized and/or listed by treatment group for the ITT population. Assessment windows for the scheduled study visits are: Visit 2 (Randomization, 7 to 14 days after Visit 1), Visit 3 (Week 1, 7± 3 days after randomization), Visit 4 (Week 2, 14± 3 days after randomization), Visit 5 (Week 3, 21± 3 days after randomization), and Visit 6 (Week 4, 28± 3 days after randomization). Individual assessments collected outside of the assessment window for scheduled visits will be included in the ITT analysis without adjustment. If multiple assessments are collected within the same assessment window, the last valid value prior to randomization will be used as the baseline value and the first valid value will be used for all post-randomization visits. 8.3.5.3.1.

Extent of Exposure

Extent of exposure to study treatment (i.e., number of days on treatment) will be summarized by treatment group using mean, standard deviation, median, minimum, and maximum. In addition, duration of subject exposed to study drug will be summarized across treatment groups. 8.3.5.3.2.

Adverse Events

Adverse events during the screening period, during the treatment period, and during the post treatment period will be summarized and displayed by treatment group. Adverse events during the screening period include those with a date of onset prior to study treatment initiation (randomization date). Adverse events during the treatment period include those with a date of onset on the date of study treatment initiation to one day after study treatment termination. The eCRF texts for adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and will be reported using the primary System Organ

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Class (SOC) and Preferred Term. Preferred Terms will be summarized within the primary SOC. The relationship of primary SOC, preferred terms, and verbatim text will be listed. The number of subjects with one or more events of any type will be calculated. Results will be displayed in the order of decreasing frequency, both across primary SOC and within primary SOC. Adverse events during the study period will also be listed. Demographic details (e.g., age, sex, and race), as well as details of the individual adverse events, will be included in these listings. Listings will be sorted within subject by the adverse event date of onset. Similar summaries and listings will be provided for drug-related adverse events, and adverse events leading to withdrawal from treatment. 8.3.5.3.3.

Deaths and Serious Adverse Events

Deaths and serious adverse events during the study period will be listed. Any pregnancies, serious adverse events and deaths reported during this study will also be summarized in case narratives written by Global Clinical Safety and Pharmacovigilance personnel. 8.3.5.3.4.

Clinical Laboratory Evaluations

The normal ranges determined by the laboratory, will be displayed. The shift from baseline in laboratory data with respect to the normal range will be summarized for each analyte. Laboratory values outside the normal ranges will also be summarized. All laboratory data will be listed for those subjects with at least one abnormal laboratory value. 8.3.5.3.5.

Nasal Examinations

Nasal examinations will be performed at each visit, and will include assessments of mucosal bleeding, ulcers, polyps, and fungal infections. Nasal examination results will be summarized by visit for each of the examination parameters listed above. At all visits, frequencies of classifications (yes/no, absent/present) will be calculated. Shift from baseline (Visit 2) to endpoint (Week 4 or Early Withdrawal visit) will also be summarized for each individual nasal examination parameter. Abnormal nasal examination results will be listed. 8.3.5.3.6.

Vital Signs

Number of subjects, mean, standard deviation, median, minimum, and maximum will be used to summarise vital signs (heart rate [pulse], systolic blood pressure, and diastolic blood pressure) by visit and treatment group.

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Health Outcomes Analyses

The primary analysis of the RQLQ(S) is the mean change from baseline in the global score compared between the treatment groups at endpoint. Scoring of the RQLQ(S) will follow the guidelines established by the authors of the instrument [Juniper, 1999]. Baseline will be defined as the Visit 2 questionnaire. Endpoint will be defined as the last available on treatment questionnaire. An analysis of covariance model including terms for treatment, country and baseline value will be used to test statistical differences in treatment group mean changes from baseline at endpoint. A mean treatment difference in change from baseline of 0.5 or more for the RQLQ(S) scores is considered a minimally important difference [Juniper, 1994]. In addition, if the difference between treatments in the global score is found to be significant, then individual domain scores between treatment groups will be compared.

9.

STUDY CONDUCT CONSIDERATIONS

9.1.

Regulatory and Ethical Considerations, Including the Informed Consent Process

Prior to initiation of a study site, GSK will obtain approval from the appropriate regulatory agency to conduct the study in accordance with applicable country-specific regulatory requirements, including those required under a US IND. The study will be conducted in accordance with all applicable regulatory requirements, including an U.S. IND. The study will be conducted in accordance with Good Clinical Practice (GCP), all applicable subject privacy requirements, and the guiding principles of the declaration of Helsinki, including, but not limited to: •

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and approval of study protocol and any subsequent amendments.

•

Subject informed consent.

•

Investigator reporting requirements.

GSK will provide full details of the above procedures, either verbally, in writing, or both. Written informed consent must be obtained from each subject prior to participation in the study.

9.2.

Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will include

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identification, agreement and documentation of data items for which the CRF will serve as the source document. GSK will monitor the study to ensure that the: •

Data are authentic, accurate, and complete.

•

Safety and rights of subjects are being protected.

•

Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

9.3.

Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss any findings/relevant issues.

9.4.

Study and Site Closure

Upon completion (last subject, last visit) or termination of the study, the GSK monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK Standard Operating Procedures. GSK reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe noncompliance. If GSK determines that such action is required, GSK will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, GSK will provide advance notice to the investigator or head of the medical institution of the impending action. If a study is suspended or terminated for safety reasons, GSK will promptly inform all investigators, heads of the medical institutions (where applicable),and/or institutions conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.

9.5.

Records Retention

Following closure of the study, the investigator or head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must - 56 -

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be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff. Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions. GSK will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK standard operating procedures, and/or institutional requirements. The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.

9.6.

Provision of Study Results and Information to Investigators

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutuallyagreeable location. Upon completion of the clinical study report, GSK will ensure public disclosure of the clinical trial research results via the GSK Clinical Trial Register and provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate. GSK will provide the investigator with the randomization codes for their site only after completion of the full statistical analysis.

9.7.

Independent Data Monitoring Committee (IDMC)

An IDMC will not be utilized in this study.

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REFERENCES

Allen A, Down G, Newland A, Reynard K, Rosell V, Salmon E, Scott R. Absolute Bioavailabilty of Intranasal Fluticasone Furoate in Healthy Subjects. Clin Ther. 2007; 29:1415-1420. American Academy of Allergy, Asthma, and Immunology (AAAAI). The Allergy Report. Task Force on Allergic Disorders, Available at www.aaaai.org.; 2000. Accessed September 10, 2007. Bende M, Carrillo T, Vona, et al. A Randomized Comparison of the Effects of Budesonide and Mometasone Furoate Aqueous Nasal Sprays on Nasal Peak Flow Rate and Symptoms in Perennial Allergic Rhinitis. Ann Allergy Asthma Immunol. 2002; 88:617-623. GlaxoSmithKline Document Number RM2004/00130/02, GW685698X. Investigator Brochure for Fluticasone Furoate: A Novel Glucocorticoid Receptor Agonist for Intranasal Use in the Treatment of Allergic Rhinitis. Report Date 03-Nov-2006. Global Initiative for Asthma (GINA). Guidelines revised 2006. Available at, ginasthma.com; 2006. Accessed July 2, 2007. Juniper EF, et al. Determining a Minimal Important Change in a Disease-Specific Quality of Life Questionnaire. J Clin Epidemiol. 1994; 47 (1):81-87. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of the Standardized Version of the Rhinoconjunctivitis Quality of Life Questionnaire. J Allergy Clin Immunol. 1999, 104:364-369. Lemiére C, Bai T, Balter M, et al, on behalf of the Canadian Adult Consensus Group of the Canadian Thoracic Society. Adult Asthma Consensus Guidelines Update 2003. Can Respir J. 2004; 11 (Suppl A):9A-18A. National Asthma Education and Prevention Program (NAEPP) Guidelines for the Diagnosis and Management of Asthma – Expert Panel Report 3, National Institutes of Health, August 28, 2007. Starling-Schwanz R, Peake HL, Salome CM, et al. Repeatability of Peak Nasal Inspiratory Flow Measurements and Utility for Assessing the Severith of Rhinitis. Allergy. 2005; 60:795-800. VERAMYST (fluticasone furoate) Prescribing Information. April, 2007. Wilson A, Dempsey OJ, Sims EJ. Evaluation of treatment Response in Patients with Seasonal Allergic Rhinitis Using Domiciliary Nasal Peak Inspiratory Flow. Clinical and Experimental Allergy. 2000; 30:833-838.

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Wilson. 2003 Review, Airflow Obstruction and Peak Nasal Inspiratory Flow (PNIF). Available at www.clement-clarke.com, Accessed September 10, 2007; 2003.

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11.

APPENDICES

11.1.

Appendix 1: PGx

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Pharmacogenetic Research Pharmacogenetics – Background Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in different populations. There is increasing evidence that an individual's genetic composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx analysis include: Drug Abacavir

Tranilast

ABT-761

Disease HIV [Hetherington, 2002; Mallal, 2002] Restenosis prevention following coronary bypass [Roses, 2002] Asthma [Drazen, 1999]

Gene HLA (human leukocyte antigen)

Outcome Caucasian males with HLA B57 variant were at increased risk for experiencing hypersensitivity to abacavir

UGT1A1

Drug induced hyperbilirubinemia explained by high proportion of affected patients having 7/7 TA repeat genotype, consistent with clinically benign Gilbert’s Syndrome

ALOX5

ALOX5 Sp1 promoter genotype (x,x) associated with reduced response to 5lipoxygenase inhibitor ABT-761

A key component to successful PGx research is the collection of samples during the conduct of clinical studies. Collection of whole blood samples, even when no a priory hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in handling or response to fluticasone furoate. Pharmacogenetic Research Objectives The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to fluticasone furoate. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with fluticasone furoate that may be attributable to genetic variations of subjects, the following objectives may be investigated:

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•

Relationship between genetic variants and the pharmacokinetics of investigational product

•

Relationship between genetic variants and safety and/or tolerability of investigational product

•

Relationship between genetic variants and efficacy of investigational product

Study Population Any subject who has given informed consent to participate in the clinical study, has met all the entry criteria for the clinical study, and receives investigational product may take part in the PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research. Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled. Study Assessments and Procedures In addition to any blood samples take for the clinical study, a whole blood sample (~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labeled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample will be taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study. If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed. The need to conduct PGx analysis may be identified after a study (or a set of studies) of fluticasone furoate has been completed and the study data reviewed. In some cases, the samples may not be studied. e.g., no questions are raised about how people respond to fluticasone furoate. Samples will be stored securely and may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. GSK or those working with GSK (for example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form. Subjects can request their sample to be destroyed at any time.

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Subject Withdrawal from Study If a subject who has consented to participate in PGx research and has a sample taken for PGx research withdraws from the clinical study for any reason other than lost to followup, the subject will be given the following options: •

The sample is retained for PGx research

•

Any PGx sample is destroyed.

If a subject withdraws consent from the PGx research or requests sample destruction for any reason, the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records. In either case, GSK will only keep study information collected/generated up to that point. Screen and Baseline Failures If a blood sample for PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records. Pharmacogenetics Analyses Generally GSK will utilize two approaches to explore genetic variation in drug response. 1.

Specific sections of DNA may be selected from areas of the genome (e.g., candidate genes) known to encode the drug target, drug metabolizing enzymes, areas associated with mechanisms underlying adverse events, and those linked to study disease and, thus, linked to drug response. The candidate genes that may be investigated in this study will include the following: the GSK Absorption, Distribution, Metabolism and Excretion (ADME) panel. Absorption, distribution, metabolism and excretion (ADME) genes play a central role in drug pharmacokinetics and pharmacodynamics (PK-PD). The GSK ADME panel contains genetic markers from one hundred and thirty-five enzymes, transporters and other genes involved in drug absorption, distribution, metabolism and excretion. The ADME panel may be used to investigate the relationship between genetic variants on the panel and pharmacokinetics, safety and efficacy of the investigational product.

2.

By evaluating large numbers of polymorphic markers (e.g., single nucleotide polymorphisms or SNPs) throughout the genome, sets of markers may be identified that correspond to differential drug response.

Hardy-Weinberg Equilibrium Testing The genotypic frequencies of each polymorphism will be evaluated for conformity to those expected under normal conditions by employing Hardy-Weinberg Equilibrium testing.

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Comparison of Demographic and Baseline Characteristics by Genotype Differences in baseline clinical characteristics and potential contributing covariates may be summarized and compared among genotype (or haplotype) subgroups. Evaluation of Genotypic Effects Analyses may be carried out to evaluate the degree of association between subject genotype (or haplotype) and selected parameters (e.g., pharmacokinetics, efficacy and safety). Where such genotypic tests are inappropriate (for example, where the number of marker genotypes is too large and/or the frequency of individual genotypes too small), allelic tests may be conducted. Allelic tests evaluate whether the frequency of each marker allele is the same in responders and non-responders. Evaluation of Treatment by Genotype and Gene-Gene Interaction In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the selected parameters, the possibility of a treatment group by genotype (haplotype or allele) interaction will also be explored. If appropriate, the joint effects of multiple markers (gene-gene interactions) may also be evaluated. Linkage Disequilibrium For pairs of polymorphisms, the degree to which alleles from the two sites are correlated (linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic sites within a gene are shown to be statistically associated with a response to investigational product, the degree of linkage disequilibrium will aid interpretation in that it will indicate the extent to which the two sites are exerting independent effects. Multiple Comparisons and Multiplicity An adjustment to observed p-values may be made to limit erroneous conclusions due to multiple tests when multiple markers are evaluated (especially in the case of a genome scan for association), Power and Sample Size Considerations The ability to detect differential drug response among genotypes at a polymorphic site depends on the total number of subjects genotyped and the frequency distribution of the different genotypes. Consequently, genotyping analyses are plausible for those polymorphic sites where the number of subjects comprising the genotypic groups is sufficiently large; however, these frequencies will not be known until sufficient samples have been collected and genotyping is complete. Estimates of sample sizes required to demonstrate genotype effects vary considerably, depending on the assumptions made about allele frequency, genetic effect size, and mechanism of inheritance [Cardon, 2000]. In the work by Palmer and Cookson [Palmer, 2001], which assumed a genotype relative risk of 1.5, it was estimated that more than 300 cases and 600 controls would be needed to conduct a genetic association - 63 -

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analysis. In contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a genotype relative risk of 2.16 and a relatively commonly occurring genotype, only 30 cases and 30 controls would be needed to demonstrate an association. Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002; Mallal, 2002] and tranilast induced hyperbilirubinemia [Roses, 2002] where genetic markers have been found to significantly associate with hypersensitivity reaction (abacavir) and hyperbilirubinemia (tranilast). These examples show that small sample sizes typically encountered in Phase I and Phase II studies may be sufficient to identify clinically relevant genetic associations. Informed Consent Subjects who do not wish to participate in the PGx research may still participate in the clinical study. PGx informed consent must be obtained prior to any blood being taken for PGx research. Provision of Study Results and Confidentiality of Subject’s PGx Data GSK may summarize the cumulative PGx research results in the clinical study report. In general, GSK does not inform the investigator, subject, or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of the PGx research results that are not known to be relevant to the subject’s medical care at the time of the study under any circumstances, unless required by law. The information generated from PGx studies is preliminary in nature, and the significance and scientific validity of the results are undetermined at such an early stage of research,. References Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics. 2000; 10:503-10. Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 1999; 22:168-70. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32.

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McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol. 2000; 18:505-8. Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respir Res. 2001; 2:102-12. Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov. 2002; 1:541-9.

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Appendix 2: Clinical Laboratory Assessments

Chemistry

Hematology

Electrolytes

Total Bilirubin Alkaline Phosphatase Alanine Amino-transferase (ALT or SGPT) Aspartate Amino-transferase (AST or SGOT) Glucose Creatinine Urea nitrogen Calcium Total Protein Albumin

Hemoglobin Hematocrit RBC WBC Neutrophils Lymphocytes Monocytes Eosinophils Basophils Platelets

Sodium Potassium

Urine pregnancy tests will be done at Visits 1, 2, 5, 6/EW for all females of childbearing potential..

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Appendix 3: Country-Specific Requirements

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RM2007/00519/01 CONFIDENTIAL CONFIDENTIAL TheGlaxoSmithKline GlaxoSmithKline of companies The groupgroup of companies

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Division: Worldwide Development Retention Category: GRS019 Information Type: Protocol Amendment Title:

A Randomized, Double-Blind, Placebo-Controlled, ParallelGroup, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR)

Compound Number:

GW685698

Effective Date:

07-JAN-2008

Protocol Amendment Number: 01 Description: The purpose of FFU111439 Amendment 01 is to make two corrections: 1.

Correct the Compound Number on Page 1 of the protocol

2.

Correct the EudraCT Number on the Sponsor Information Page (Page 3)

Subject: Perennial Allergic Rhinitis, fluticasone furoate nasal spray, GW685698X, EudraCT Number Author: Revision Chronology: RM2007/00519/00

2007-OCT-25

Original

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2008-JAN-07

Amendment No.:01 Correct the Compound Number on Page 1 and the EudraCT Number on the Sponsor Information Page (Page 3)

Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

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INVESTIGATOR AGREEMENT PAGE I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

Investigator Name: _____________________________

Investigator Signature

Date

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Rationale The objective of the amendment is to correct the Compound Number on Page 1 and the EudraCT Number on the Sponsor Information Page (page 3) in the original protocol. Amendment 01 applies to all countries and all sites participating in FFU111439.

Original Verbatim Text Page 1 of original protocol: Compound Number: GW685968X

Amended Text Compound Number: GW685698X

Original Verbatim Text Page 3 of original protocol – Sponsor Information Page EudraCT Number: 2007-005136-89

Amended Text EudraCT Number: 2007-006562-15

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GSK FFU111439 Protocol PHT Corporation eDiary System LogPad Subject Diary Instruction Card

Page 1 of 2

Thank you for your participation in the GSK FFU111439 Protocol, utilizing PHT’s LogPad eDiary to enter your daily diaries! Accessing Your Daily Diaries Each day after you receive your LogPad, buttons will appear on the main screen when your daily assessments are available to be completed. They are as follows: Morning Diary – 5:00 am to Noon Evening Diary – 5:00 pm to Midnight _____________________ Please be sure to complete your diaries within the time window each day!

PHT Study Support Center During office hours, call your Study Coordinator if you have questions or problems using the LogPad. On weekends or evenings, you may contact the Study Support Center at:

Live coverage is available 9am through 11pm Central Time. Between 11pm and 9am, you may leave a message and Study Support will return your call within ½ an hour. Please have the following information available when you call: Sponsor Name: GSK Protocol Number: FFU111439 Subject ID: Displayed on the main screen of your LogPad

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Question Response Tips 1.

Please complete all morning assessments first thing as soon as you wake up.

2.

Please complete all morning assessments before taking your study drug.

3.

Remember! Click on SEND button after completion of the assessments.

Send Now: Transmits assessment to PHT immediately. Send Later: Stores assessment on LogPad. You may complete an additional assessment and send both at the same time.

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Completing Your Diaries General Questions Q. How do I turn on the LogPad? A. To turn on the LogPad, push the Power button, which is located on the top right side of the unit.

Q. What if I have trouble completing or sending the diary, or problems with the equipment? A. Please check out the Quick Start Guide included in the front cover of your LogPad for tips on working with the device. If you need additional assistance, please call PHT Study Support.

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Note: Once you have drawn a check mark at a signature screen and tapped , you cannot go back to change your answers even if you have not sent the data. Soft taps on the LogPad screen with the stylus are sufficient to select a response, select a check box or write a check mark to confirm your diary report. On screens where there are multiple choices for a response, the response you select is highlighted.

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English PRC v1.08; LP Spec vX.yy

Evening Diary Screen Number Evening Diary ED_1_0 (c)

English

Evening Diary ED_1_0 (d) Resp 0

Evening Diary ED_1_0 (d) Resp 1

Evening Diary ED_1_0 (d) Resp 2

Evening Diary ED_1_0 (d) Resp 3

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Evening Diary ED_2_0 (b) Resp 0

Evening Diary ED_2_0 (b) Resp 1

Evening Diary ED_2_0 (b) Resp 2

Evening Diary ED_2_0 (b) Resp 3

Evening Diary ED_3_0

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GSK / FFU111439 3 Jan 2008 Screen Number Evening Diary ED_3_0 (b) Resp 0

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Evening Diary ED_3_0 (b) Resp 1

Evening Diary ED_3_0 (b) Resp 2

Evening Diary ED_3_0 (b) Resp 3

Evening Diary ED_4_0

Evening Diary ED_4_0 (b) Resp 0

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GSK / FFU111439 3 Jan 2008 Screen Number Evening Diary ED_4_0 (b) Resp 1

RM2008/00422/00

English PRC v1.08; LP Spec vX.yy English

Evening Diary ED_4_0 (b) Resp 2

Evening Diary ED_4_0 (b) Resp 3

Evening Diary ED_5_0

Evening Diary ED_5_0 (b) Resp 0

Evening Diary ED_5_0 (b) Resp 1

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Comments

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Evening Diary ED_5_0 (b) Resp 2

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English PRC v1.08; LP Spec vX.yy English

Evening Diary ED_5_0 (b) Resp 3

Evening Diary ED_6_0

Evening Diary ED_6_0 (b) Resp 0

Evening Diary ED_6_0 (b) Resp 1

Evening Diary ED_6_0 (b) Resp 2

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Comments

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Evening Diary ED_6_0 (b) Resp 3

RM2008/00422/00

English PRC v1.08; LP Spec vX.yy English

Evening Diary ED_7_0

Evening Diary ED_7_0 (b) Resp 0

Evening Diary ED_7_0 (b) Resp 1

Evening Diary ED_7_0 (b) Resp 2

Evening Diary ED_7_0 (b) Resp 3

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Comments

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008

English PRC v1.08; LP Spec vX.yy

Screen Number Evening Diary ED_8_0

English

Evening Diary ED_9_0

Individual Access Codes Screen Number Individual Access Codes RSAC1_0 (c)

RM2008/00422/00

English

Comments

Individual Access Codes RSAC1_5

Individual Access Codes RSAC2_0

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Comments

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Individual Access Codes RSAC2_3 (b)

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English PRC v1.08; LP Spec vX.yy English

Comments

Individual Access Codes RSAC2_4

Individual Access Codes RSAC3_0

Individual Access Codes RSAC4_0

Individual Access Codes RSAC5_0 (b)

Individual Access Codes RSAC5_2

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Individual Access Codes RSAC5_4

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English PRC v1.08; LP Spec vX.yy English

Comments

Individual Access Codes RSAC6_0 (b)

Individual Access Codes RSAC6_2

Individual Access Codes RSAC7_0

Individual Access Codes RSAC7_5

Individual Access Codes RSAC8_0

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Individual Access Codes RSAC9_0

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English PRC v1.08; LP Spec vX.yy English

Comments

Individual Access Codes RSAC9_2

Individual Access Codes RSAC10_0

Individual Access Codes RSAC10_5

Individual Access Codes RSAC11_0

Individual Access Codes RSAC11_5

Page 10 of 24

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Individual Access Codes RSAC12_0

English PRC v1.08; LP Spec vX.yy English

Comments

English

Comments

Morning Diary Screen Number Morning Diary MD_1_0 (c)

RM2008/00422/00

Morning Diary MD_1_0 (d) Resp 0

Morning Diary MD_1_0 (d) Resp 1

Morning Diary MD_1_0 (d) Resp 2

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number English Morning Diary MD_1_0 (d) Resp 3

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English PRC v1.08; LP Spec vX.yy Comments

Morning Diary MD_2_0

Morning Diary MD_2_0 (b) Resp 0

Morning Diary MD_2_0 (b) Resp 1

Morning Diary MD_2_0 (b) Resp 2

Morning Diary MD_2_0 (b) Resp 3

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Morning Diary MD_3_0

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English PRC v1.08; LP Spec vX.yy English

Comments

Morning Diary MD_3_0 (b) Resp 0

Morning Diary MD_3_0 (b) Resp 1

Morning Diary MD_3_0 (b) Resp 2

Morning Diary MD_3_0 (b) Resp 3

Morning Diary MD_4_0

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number English Morning Diary MD_4_0 (b) Resp 0

RM2008/00422/00

English PRC v1.08; LP Spec vX.yy Comments

Morning Diary MD_4_0 (b) Resp 1

Morning Diary MD_4_0 (b) Resp 2

Morning Diary MD_4_0 (b) Resp 3

Morning Diary MD_5_0

Morning Diary MD_5_0 (b) Resp 0

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number English Morning Diary MD_5_0 (b) Resp 1

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English PRC v1.08; LP Spec vX.yy Comments

Morning Diary MD_5_0 (b) Resp 2

Morning Diary MD_5_0 (b) Resp 3

Morning Diary MD_6_0

Morning Diary MD_6_0 (b) Resp 0

Morning Diary MD_6_0 (b) Resp 1

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number English Morning Diary MD_6_0 (b) Resp 2

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English PRC v1.08; LP Spec vX.yy Comments

Morning Diary MD_6_0 (b) Resp 3

Morning Diary MD_7_0

Morning Diary MD_7_0 (b) Resp 0

Morning Diary MD_7_0 (b) Resp 1

Morning Diary MD_7_0 (b) Resp 2

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number English Morning Diary MD_7_0 (b) Resp 3

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English PRC v1.08; LP Spec vX.yy Comments

Morning Diary MD_8_0

Morning Diary MD_8_0 (b) Resp 0

Morning Diary MD_8_0 (b) Resp 1

Morning Diary MD_8_0 (b) Resp 2

Morning Diary MD_8_0 (b) Resp 3

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147

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Morning Diary MD_9_0

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English PRC v1.08; LP Spec vX.yy English

Comments

Morning Diary MD_9_0 (b) Resp 0

Morning Diary MD_9_0 (b) Resp 1

Morning Diary MD_9_0 (b) Resp 2

Morning Diary MD_9_0 (b) Resp 3

Morning Diary MD_10_0

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Morning Diary MD_10_0 (b) Resp 0

RM2008/00422/00

English PRC v1.08; LP Spec vX.yy English

Comments

Morning Diary MD_10_0 (b) Resp 1

Morning Diary MD_10_0 (b) Resp 2

Morning Diary MD_10_0 (b) Resp 3

Morning Diary MD_11_0

Morning Diary MD_11_0 (b) Resp 0

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149

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Morning Diary MD_11_0 (b) Resp 1

RM2008/00422/00

English PRC v1.08; LP Spec vX.yy English

Comments

Morning Diary MD_11_0 (b) Resp 2

Morning Diary MD_11_0 (b) Resp 3

Morning Diary MD_12_0

Morning Diary MD_12_0 (b) Resp 0

Morning Diary MD_12_0 (b) Resp 1

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Morning Diary MD_12_0 (b) Resp 2

RM2008/00422/00

English PRC v1.08; LP Spec vX.yy English

Comments

Morning Diary MD_12_0 (b) Resp 3

Morning Diary MD_13_0

Morning Diary MD_13_0 (b) Resp 0

Morning Diary MD_13_0 (b) Resp 1

Morning Diary MD_13_0 (b) Resp 2

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151

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Morning Diary MD_13_0 (b) Resp 3

RM2008/00422/00

English PRC v1.08; LP Spec vX.yy English

Comments

Morning Diary MD_14_0

Morning Diary MD_14_0 (b) Resp 0

Morning Diary MD_14_0 (b) Resp 1

Morning Diary MD_14_0 (b) Resp 2

Morning Diary MD_14_0 (b) Resp 3

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152

CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Morning Diary MD_15_0

English PRC v1.08; LP Spec vX.yy English

Comments

Morning Diary MD_15_5

Morning Diary MD_16_0

Morning Diary MD_17_0

Utilities_Subject Screen Number Utilities_Subject-1

RM2008/00422/00

English

Comments

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CONFIDENTIAL

GSK / FFU111439 3 Jan 2008 Screen Number Utilities_Subject1b

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English PRC v1.08; LP Spec vX.yy English

Comments

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CONFIDENTIAL FFU111439

LIST OF INVESTIGATORS AND IECS/IRBS FOR FFU111439 (RM2008/00422/00) Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

CANADA Canada Canada Canada

Canada

Canada

Canada

Canada

CONFIDENTIAL

1

Canada

Canada

Canada

1

Canada

RM2008/00422/00

Canada

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

Canada Canada

Canada

2

Canada

Canada

Canada

CONFIDENTIAL

Canada Dr.

Canada

RM2008/00422/00

2

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

ESTONIA

Estonia Estonia

3

Estonia GERMANY

CONFIDENTIAL

Estonia

Germany Germany PD Dr.

Germany Dr.

3

RM2008/00422/00

Germany

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

Germany Germany HUNGARY Hungary

Hungary 4

Hungary Dr Hungary

4

Hungary Dr

Hungary Dr

RM2008/00422/00

Hungary

CONFIDENTIAL

Dr

Hungary

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

RUSSIA

Russia.

Russia.

CONFIDENTIAL

Russia.

RM2008/00422/00

5

Russia.

Russia.

5

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

Russia. Russia.

CONFIDENTIAL

Russia. SLOVAKIA 6 Slovak Republic

Slovak Republic MD

RM2008/00422/00

6

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

Slovak Republic Slovak Republic

MD 7 Slovak Republic

Slovak Republic

MD

7

RM2008/00422/00

Slovak Republic

CONFIDENTIAL

Slovak Republic

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

UNITED STATES

CONFIDENTIAL

8

RM2008/00422/00

8

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of Committee

CONFIDENTIAL

9

RM2008/00422/00

9

CONFIDENTIAL FFU111439

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

10

CONFIDENTIAL

*Did not screen or randomise any subjects. **Did not randomise any subjects.

IEC/IRB Committee Chair and Name of Committee

RM2008/00422/00

10

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy.

CONFIDENTIAL

RM2008/00422/00

Subject Information and Consent Form and Information Sheet for Pharmacogenetic Research Research Study Title:

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) A Clinical Study to Test a Nasal Spray (fluticasone furoate nasal spray) for the Treatment of Perennial (year-round) Allergic Rhinitis

Protocol#:

FFU111439

Sponsor:

GlaxoSmithKline

Subject Identification:

_________________________________

Principal Investigator:

«FirstName» «MiddleName» «LastName» «Suffix»

Address(es): «Company» «Address» «SuiteDept» «City» «State» «Zip»

«Company2» «Address2» «City2» «State2» «Zip2»

«Company3» «Address3» «City3» «State3» «Zip3»

«Company4» «Address4» «City4» «State4» «Zip4»

«Company5» «Address5» «City5» «State5» «Zip5»

Daytime telephone number(s): «Phone» 24-hour contact number(s):

«Phone2»

Who does this consent form apply to? This consent form could apply to you or to your child as a subject. Throughout this form use of “you/your” refers to “you or your child/your or your child’s”, and “I” refers to “I or my child.” This form is in addition to the consent form you signed for the clinical study for fluticasone furoate nasal spray. All of the information in the Subject Information and Consent Form and Authorization to Use and Disclose Personal Health Information for Research still applies.

Page 1 of 7 FFU111439

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Purpose and Description of the Research The purpose of this consent form is to explain what pharmacogenetic research is and to ask you to give a blood sample that may be used in this research. The sponsor of the research is the GlaxoSmithKline group of companies [referred to as GSK in this consent]. The study doctor and/or institution are paid by GSK to conduct this research. This study may have about 288 subjects at about 40 - 50 sites in North America and Europe. What is pharmacogenetic research? Genes, which we inherit from our parents, may control the way we react to or handle a medicine. Pharmacogenetics is the study of differences in how our bodies respond to or handle medicines. This pharmacogenetic research is looking at genetic differences to better understand why people react differently when they get the same medicine. If it appears that there is a difference in the way people respond to or handle fluticasone furoate nasal spray, GSK may study these differences using your genes or genetic material taken from your blood sample. What exactly will participation in the research involve? If you choose to take part in this research, a qualified medical worker will take about 10 ml (or 2 teaspoons) of your blood. In the unlikely case that there is a problem processing your sample, then we may ask you to give a second sample. What are the risks involved with blood sampling? The physical risks of giving a blood sample are the same as those for any blood sample taken from a vein. You may feel faint, experience mild pain, bruising, irritation or redness at the site of puncture. In rare cases an infection could develop. What are the benefits of participating in this research study? There will be no direct benefit to you by taking part in this pharmacogenetic research. You may help scientists understand why people react to or handle fluticasone furoate nasal spray differently. This may help identify who is more likely to respond to fluticasone furoate nasal spray and who may experience side effects. Will there be compensation for participation in the research? You will not receive any payment for taking part in this pharmacogenetic research. OR You will be paid $_____ for your time and travel related expenses. What other options are there? You have the choice not to take part in this research. Compensation for Study-Related Injury If you are physically injured by the properly performed blood draw and you have followed the directions of the study staff, the sponsor will cover the reasonable medical expenses necessary to treat the injury. No other compensation is offered by GSK, but you do not waive any legal rights by signing this consent form.

Is participation in this study voluntary? Page 2 of 7 FFU111439

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Participation in this pharmacogenetic research is voluntary. You may decline to take part now or you may decide to take part and then change your mind. GSK may store your sample for up to 15 years after the last subject completes the study or GSK may destroy your sample at an earlier time. If you decide not to participate or to withdraw your consent after starting the study, you do not have to give a reason and there will be no change to your medical treatment or to your participation in the fluticasone furoate nasal spray study. If you withdraw from this research, your sample will be destroyed and GSK will only keep study information collected/generated up to that point. In special cases, your sample may not be used. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond to or handle fluticasone furoate nasal spray. How are privacy, data protection and confidentiality protected? As part of the clinical trial, medical information will be collected and analyzed. To protect your privacy, your sample and medical information will be labeled (or “coded”) with a study subject number, not your name. Only your study doctor and his or her staff will keep the link between your subject number and your name. GSK will control access to its files that hold your coded information and results. Your name will not appear in any publications or reports about this research. GSK or those working with GSK (for example, other researchers) will only work with your sample for the use stated in this consent. Samples will be stored securely. GSK will require anyone who works with your sample to agree to hold the research information and any individual results in confidence. Medical information about you may be produced as part of the research or study procedures. If at the time of the study, this information is known to be relevant to your medical care it will be given to the study doctor who will be encouraged to share it with you or your doctor. You will be told if any of this medical information requires confirmation using a clinical test. This is important because some research results are for research purposes and may have only limited relevance for clinical diagnosis or treatment. Individual research results that are not known to be relevant to your medical care at the time of the study will not be released to anyone, unless required by a governmental agency or other legal authority. “Anyone” includes you, your family, your doctor, your insurance company, and your employer. GSK has taken appropriate measures to ensure the confidentiality of the research-related information. However, if you pass on your individual results (if obtained by you), there is a possibility that this could have an effect on your insurance or employment. This risk is similar as if you were to disclose any type of personal medical information to a third party. Medical information, samples and research results from you and other research participants may be studied by GSK to make medicines or tests to determine the body’s response to or handling of Page 3 of 7 FFU111439

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Subject’s Initials _____

CONFIDENTIAL

RM2008/00422/00

medicine. Your information and any results will be put in a computer and stored in electronic databases. International regulations for information on computers and relevant laws on processing personal information will be strictly adhered to. Your information, sample, and results could be sent to other researchers working with GSK and to other GSK sites. By agreeing to take part in this research, you will allow your medical information, sample, and pharmacogenetic results to be reviewed as part of collecting and analyzing study results. The people who may check this research include GSK, people working with GSK on this research, ethics committees/institutional review boards, and regulatory authorities, such as the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA). These persons are required to maintain the confidentiality of the information. Disclosure of Protected Health Information Authorization to use or disclose your medical information as described above does not have an expiration (ending) date. ***will expire December 31, 2050. FOR WA and CA sites***. If you decide not to sign this consent, you will not be included in the study. You may withdraw this authorization at any time in writing. If you sign this consent and decide later to withdraw the authorization, you will be withdrawn from the study at that time. Information collected up to the time you withdraw your authorization will continue to be used as study data. Once information is disclosed under this authorization to someone who is not a health care provider, the information is no longer protected by the US privacy rules (called the HIPAA privacy regulations) and could be disclosed to others by the recipient. Commercial Issues GSK and/or others intend to claim sole ownership of any research results consistent with this consent. The results of this research may have commercial or intellectual property value. By signing this consent, you agree that GSK can apply for patents and you understand that you will not receive any financial benefit that might come from the research. Who can you call for more information about this research study? If you have any questions about your participation in this research study, or if you feel that you have experienced a research-related injury related to the blood draw for this research, or wish to withdraw from this research, contact: Principal Investigator:

«FirstName» «MiddleName» «LastName» «Suffix»

Daytime telephone number(s): «Phone» 24-hour contact number(s):

«Phone2»

If you have questions about your rights as a research subject, you may contact (toll free). An IRB is a group of scientific and non-scientific individuals who perform the initial and ongoing ethical review of the research Page 4 of 7 FFU111439

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Subject’s Initials _____

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RM2008/00422/00

study with the study subject's safety and welfare in mind. If you have study-related comments, complaints or concerns, you should first contact the study investigator. Please call the IRB if you want to talk to someone other than the study investigator or have difficulty reaching the study investigator. For further information regarding the clinical trials process and your role as a research subject, you may visit the

Page 5 of 7 FFU111439

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Subject’s Initials _____

CONFIDENTIAL

RM2008/00422/00

CONSENT A copy of this Consent Form (signed and dated) must be given to the subject or legal representative. My signature below indicates that: 1. 2. 3. 4.

I have read this form and the research has been explained to me. I have been able to discuss the research and ask questions. I am satisfied with the answers. I have been given the time to consider whether or not to take part in this research. I have freely decided to take part in the research study described in this form.

Subject’s Name (Please Print): __________________________________

Subject’s Signature: _______________________________________ Date: ____________ (or that of Legally Acceptable Representative) (Day/Month/Year) *Legally Acceptable Representative Name (Please Print): _______________________________________ *Description of Legally Acceptable Representative, i.e., parent/guardian, etc.: ____________________________________________________________________________

Name and Signature of Individual Obtaining the Subject’s Consent: Name (Please Print): _________________________________

Signature: ________________________________________________ Date: ____________ (Day/Month/Year) *Name and Signature of Independent Witness Name (Please Print): _________________________________

Signature: ________________________________________________ Date: ____________ (Day/Month/Year) *If applicable

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RM2008/00422/00

CONFIDENTIAL

Subject’s Statement of Assent (when subject is a minor) You are being asked to be in a research study. You do not have to be in this study. You may decide to participate or not. Even though your parents/guardians may say it is okay, you don’t have to participate if you do not want to. If there is anything you do not understand about the study after reading this information, please ask your study doctor or study staff member. If you have not had a chance to speak with the study doctor or staff without your parent(s)/guardian(s) and would like to do so, please ask to speak with them alone. They will talk to you in private. If you do not want to be a part of this study, tell the study doctor or study staff and your doctor will keep taking care of you as s/he did before. You can stop being in this study any time for any reason. No one will be upset if you stop participating in this study or don’t want to be in it. I agree to participate in this study.

Subject's Signature

_____________________________

Date:

_________ DD/ MM/ YY

Printed name of Subject

_____________________________

Page 7 of 7 FFU111439

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CONFIDENTIAL

RM2008/00422/00

Subject Information and Consent/Assent Form and Authorization to Use and Disclose Personal Health Information Research Study Title:

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) A Clinical Study to Test a Nasal Spray (fluticasone furoate nasal spray) for the Treatment of Perennial (year-round) Allergic Rhinitis

Protocol#:

FFU111439

Sponsor:

GlaxoSmithKline

Subject Identification:

_________________________________

Principal Investigator:

«FirstName» «MiddleName» «LastName» «Suffix»

Address(es): «Company» «Address» «SuiteDept» «City» «State» «Zip»

«Company2» «Address2» «City2» «State2» «Zip2»

«Company3» «Address3» «City3» «State3» «Zip3»

«Company4» «Address4» «City4» «State4» «Zip4»

«Company5» «Address5» «City5» «State5» «Zip5»

Daytime telephone number(s): «Phone» 24-hour contact number(s):

«Phone2»

Who does this consent form apply to? This consent form could apply to you or to your child as a subject. Throughout this form use of “you/your” refers to “you or your child/your or your child’s”, and “I” refers to “I or my child.” What does giving consent mean? This Subject Information and Consent Form may contain words you do not understand. Please ask the study doctor or the study staff to explain any words or procedures that you do not clearly understand.

1 of 13 FFU111439

Subject’s Initials _____

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CONFIDENTIAL

RM2008/00422/00

The purpose of this form is to give you information about the research study and, if signed, will give your permission to take part in the study. The form describes the purpose, procedures, benefits, risks, discomforts and precautions of the research study. You should take part in the study only if you want to do so. You may refuse to take part or withdraw from this study at any time without penalty or loss of benefits to which you are otherwise entitled. Please read this Subject Information and Consent Form and ask as many questions as needed. You should not sign this form if you have any questions that have not been answered to your satisfaction. How is GlaxoSmithKline involved? The study doctors and/or the institutions are paid by GlaxoSmithKline (GSK) to conduct this research study. Why is this study being done? You have been asked to take part in a clinical research study testing a nasal spray because you have been diagnosed with perennial (year-round) allergic rhinitis (runny/stuffy/itchy nose; itching/burning/tearing/watering/redness eyes due to allergies). Perennial Allergic Rhinitis (PAR) is a type of allergic rhinitis that is triggered by allergens year-round. The allergens that cause PAR are part of most household environments including animal dander from household pets, house dust mites, cockroach and mold spores. The purpose of this study is to compare the effects (effectiveness and safety) of an intranasal corticosteroid (fluticasone furoate nasal spray [FFNS]), with a placebo nasal spray for the treatment of your perennial (year-round) allergic rhinitis. FFNS, marketed as VERAMYST™ in the United States, has been approved by the United States Food and Drug Administration (FDA) for the treatment of the symptoms of seasonal and perennial allergic rhinitis in adults and children two years of age and older. FFNS is an intranasal corticosteriod for administration by the intranasal route only. The placebo nasal spray has no medicine in it. How many other subjects are there in the study? The study will involve approximately 288 subjects at 40 - 50 clinics in North America and Europe. Your study doctor will inform you if this total is reached for the study and whether your participation in the study will be required. What will my responsibilities be during the study? Your informed consent must be given before any study-related activities are started. Your study doctor will review with you what medications you may use before and during the study. You will not be allowed to take any medications for allergies before and during the study. This is necessary so we can fully measure the effects of FFNS without any interference from other medications. The time period required to stop your medicine varies by the type of medicine you take. Your doctor will tell you what that period of time is for your particular medication. You will not be allowed to use or take any other treatments unless the study doctor thinks it is medically necessary. This includes prescription and non-prescription medications, ocular (eye) preparations (medicines, artificial tears, lubricants, eye washes), and non-drug therapies (e.g., Breathe Right nasal strips, humidifiers). If you have any questions about your medicines, call your study doctor or study nurse.

2 of 13 FFU111439

Subject’s Initials _____

9

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You will be asked not to make any changes in your environment during the study (e.g., if you have a pet at the start of the study, you should keep the pet during the study). The purpose of this restriction is to be sure of continued exposure to the allergen causing your allergy symptoms. Please contact your study doctor if you need to travel outside your local home area. You will be required to record nasal and eye allergic rhinitis symptoms, as well as peak nasal inspiratory flow (PNIF) measurements on an electronic diary every morning and evening. The study staff will show you how to use the electronic diary, PNIF meter and face mask. You will also be given instructions by the study staff regarding the care and cleaning of the PNIF face mask. Between the first and second visit, you will record the symptoms you experience. After the second visit, you will record how your symptoms are after taking your assigned study treatment. At the second and last visits, you will be asked to complete a questionnaire about how your symptoms are affecting your daily life and your sleep. Your participation in the study may be stopped for any of the following reasons: • • • • • •

if you do not follow the study doctor’s instructions, the study doctor decides it is in the best interest of your health and welfare to discontinue, if you become pregnant, there are not enough subjects in the study, or the study has reached the required number of subjects, GlaxoSmithKline stops the study at this study site for other reasons not known now, GlaxoSmithKline stops enrolling new subjects into the study for any reason, and you are in the screening phase of the study and not yet assigned to a treatment group.

What does the study involve? If you agree to take part in this study, you will first sign this Subject Information and Consent Form before any study-related procedures are performed, including discontinuation of any disallowed medications. FFNS is an intranasal corticosteroid. Intranasal corticosteroids decrease the inflammation (swelling) in the nose. The medicine is contained in the nasal sprayer. If you agree to take part in this study and meet the entrance requirements, you will be assigned to receive one of these two treatments: • •

Fluticasone furoate nasal spray (FFNS) 110mcg once a day Placebo nasal spray once a day

Subjects in the study will be assigned one of the two treatments by chance (like flipping a coin). In this study, you will have a 50% (1 out of 2) chance of receiving the placebo nasal spray. The treatment is assigned by a computer that has no information about you or any other participant. The treatments will be “double-blinded”, meaning that neither you nor the doctor or study personnel will know which treatment you have taken until the study is over and all subjects have completed the study. This information can be obtained, however, if it becomes medically necessary to know which treatment you are taking during the course of the study. 3 of 13 FFU111439

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If you participate in the study and meet the entrance requirements, a treatment container containing a nasal spray will be provided to you. At the second visit to the study doctor, you will be asked to spray two sprays into each nostril. You will need to repeat this procedure each day for the duration of the study. You will be given instructions by your study doctor on how to use the nasal spray. How long will I be in the study and what procedures will be done? You are being asked to participate in the study for approximately 5 to 6 weeks. You will receive study treatment for approximately 4 weeks. During this time, you will need to visit the clinic at least 6 times. After the final visit to the clinic (last visit), your study doctor or staff will contact you or your child once more by telephone within 3 to 5 days to see how you are doing. Tests/procedures will be done at specific times during the study at the clinic to determine if you are eligible to participate in the study and to monitor your general health as well as your perennial (year-round) allergic rhinitis. After all of the screening tests are completed at the first visit, the doctor will decide if you can enter the “evaluation period” which may last for 7 to 14 days and ends when you return to the doctor’s office at the second visit. The purpose of the evaluation period is to determine if you are eligible to participate in the treatment period of the study. If the doctor determines that you are eligible for the study, you will use the nasal spray for approximately 4 weeks. Information obtained and/or tests done during this evaluation period may show that you cannot be in this study. On the second visit, you will need to come to the clinic during the morning. You will also be required to record nasal and eye allergic rhinitis symptoms, as well as peak nasal inspiratory flow (PNIF) measurements on an electronic diary. You will be asked to record your nasal and eye allergic rhinitis symptoms and the PNIF measurements on the electronic diary every morning and evening. The portable hand-held PNIF meter measures the severity of your nasal congestion. When you inhale through your nose into the latex-free face mask attached to the PNIF meter, it will measure how quickly the air can move through the nose when inhaling forcefully. The tests and procedures that will be done during the study are outlined below: • • • • • •

You will be asked to describe your past and present medical conditions and any medications you are taking at each visit. Pulse and blood pressure will be measured at the first and last visits. A physical examination will be performed at the first and last visits. An examination of the nose will be performed at every visit. A skin test for allergy (if not done during the last 12 months) will be performed at the first visit. Samples of blood will be taken from the arm at two of the visits during the study: • At the first visit, a blood sample (about one tablespoon) will be taken to help your study doctor decide if you are eligible to be in the study and to monitor your health. • At the last visit, a blood sample will also be taken to monitor your general health. 4 of 13

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•

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A test (electrocardiogram or ECG/EKG) to evaluate the electrical activity of your heart (rhythm) will be performed on you at the first visit. A urine pregnancy test will be done at Visits 1, 2, 5, and 6/Early Withdrawal for all females of childbearing potential. The result of the urine pregnancy test will be shared with the subject. The results will also be shared with the parent/guardian of a minor subject if required by state law. You will be telephoned approximately 3-5 days after finishing the study to check to see how you are feeling.

What are the foreseeable risks for taking part in the study? During this study your symptoms of allergic rhinitis could get better, worse or may not change. Throughout the study you will not be allowed to treat your allergic rhinitis with anything but the nasal spray. All drugs may cause side effects in some people. In the studies to support the marketing approval of FFNS, the following side effects occurred more commonly in people receiving FFNS than in people receiving placebo: • • • • • • •

headache, nose bleeds, throat pain, nasal ulcers, back pain, fever, and cough

In a 12-month study, nose bleed occurred in 20 out of 100 people treated with FFNS and 8 out of 100 people treated with placebo. If you have severe liver disease or are taking medicine that is broken down by the liver like the medicine ritonavir, you should not participate in the study. The study treatment should not be taken by anyone known to have allergies to any of the product's ingredients. To participate in the study, you must have received allergy skin testing in the past 12 months to verify your allergy. If not, allergy testing must be performed at the first visit. Allergy testing can make your arm itch and burn where the test was done and may cause mild pain from the needle prick. In very rare cases, you might have anaphylaxis, a whole-body allergic reaction that may cause shortness of breath, hives, swelling of the skin or tongue, itchy skin, a decrease in blood pressure and can cause death. Emergency care is available to treat this rare reaction should it occur. You will need to remain in the study office for at least 20 minutes after the skin test is performed to make sure that you do not experience a severe reaction. An ECG measures the electrical activity of the heart. An ECG requires placement of electrical sensors on your chest near your heart, on your wrists, and on your ankles. You may experience temporary discomfort (pulling on the skin/skin hair) during removal of the sensors.

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During this study you will also have samples of your blood taken. Blood samples are obtained by inserting a needle into a vein and can cause discomfort and may result in bruising, clotting, or rarely, infection. Both discomfort and bruising should disappear in a few days. What are the reproductive risks? Because the effects of FFNS on the unborn child or nursing baby/infant are uncertain, you will not be allowed to enter this study if you are pregnant or breastfeeding. If you choose to participate in this study, and are a female of childbearing potential, you must use one of the allowed contraceptive methods (a way to prevent you from becoming pregnant) for the specified period of time before and during the study. Ask your study doctor if you have any questions about these choices and which might be best for you. • • • • • • • • •

Abstinence (no intercourse) Oral contraceptive (either combined estrogen/progestin or progestin only), Injectable progestogen, Implants of levonorgestrel, Percutaneous contraceptive patches, Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year, Male partner who is sterile (vasectomy with documentation of azospermia) prior to the female subject’s entry into the study and is the sole sexual partner for that female subject, Double barrier method–condom or occlusive cap (diaphragm or cervical /vault caps) plus spermicide, Estrogenic vaginal ring

Females of childbearing potential who are not sexually active must commit to complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of six days). Female subjects should not be enrolled if they plan to become pregnant during the time of study participation. Even when you use one of the allowed contraceptive methods, there may be a small risk that you could become pregnant. Because of this, a urine pregnancy test will be done at Visits 1, 2, 5, and 6/Early Withdrawal for all females of childbearing potential. If one of these tests shows that you have become pregnant, your unborn baby may have been exposed to FFNS even if you stop taking the drug right away. If you think you are pregnant or may become pregnant, you must tell your study doctor as soon as possible. If you should become pregnant during the study you will be required to withdraw from the study. Your study doctor will arrange an Early Withdrawal visit for you and will follow your progress up to 8 weeks following delivery or to the termination of your pregnancy.

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Are there any benefits for taking part in the study? If you agree to participate in this study, the FFNS may help to treat your allergic rhinitis. The placebo nasal spray has no medicine in it. What if new information about the study drug becomes available during the study? Sometimes during the course of a research project, new information becomes available about the treatment/drug that is being studied. If this happens, we will tell you about new information that may affect your willingness to stay in this study. You may contact the study doctor at any time after your participation ends to find out if any new information about this study has become available. What payments will be made for the study? The Board approved a $100 MAX/visit To help cover the costs of participating in this study, subjects will be paid for their participation in the study. You will be paid $«MaxVisit».00 per visit for a total of $«MaxTotal».00 if you complete this study. If you withdraw or are discontinued before completing this study, or if the study ends early, you will receive a partial payment based upon the number of visits completed. Taking part in the study may lead to added costs to you that may not be reimbursed. Please ask the study doctor/staff about the likely added costs. Are there any alternative treatments? You do not have to participate in this study to receive treatment for your perennial allergic rhinitis. There are several antihistamines approved for general use in the United States (US) by the Food and Drug Administration (FDA) for the treatment of perennial and seasonal allergic rhinitis. Some alternative medications include Claritin, Clarinex, Allegra, and Zyrtec. Fluticasone furoate (marketed as Veramyst™), Nasonex, and Rhinocort are corticosteroid nasal sprays that are approved by the US Food and Drug Administration for the treatment of symptoms of perennial and seasonal allergic rhinitis. Before deciding whether or not to take part in this study, you may wish to consider other treatment options for allergic rhinitis that include intranasal corticosteroids, oral antihistamines or decongestants. Your study doctor will describe these to you based on your medical history and the treatment you have received to date. Confidentiality and Release of Medical Records If you decide to participate in the study, the study doctor and staff will collect medical and personal information about you as part of doing the study. People who work for or with GSK, and others like the or regulatory authorities responsible for approving medicines, will have access to this information at the site in order to check that the study is done properly. GSK staff who see this information at the site will keep it confidential. The study site will also transfer to GSK some of the information it collects, in a coded form. The information transferred will not include your name, initials, address, or other direct identifiers. It will be assigned a code number that only the site can connect back to your name.

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In the event you are injured in the study what compensation will be available? If you are injured as a result of the study drugs or study procedures performed during your participation in this research study, you should seek medical attention at the medical provider of your choice. If you are injured by the investigational medicine being studied or by any procedure that is done to you as specified by the study, the Sponsor will cover the medical expenses necessary to treat the injury only to the extent that such costs are not covered by your health insurance policy, by a government program, or by any other third party. You must follow the directions of the study doctor to be eligible for this coverage. Neither the Sponsor nor the study doctor has a program in place to provide other compensation in the event of an injury. What are my legal rights? You do not waive any legal rights by signing this consent and authorization form. Who will have access to medical and personal information about you that is collected in this study? You should know that once identifiable medical information about you is given to someone that is not a health care provider, it is not protected by the US federal privacy rules called the HIPAA Privacy Regulations. Medical information about you may be produced as part of the research or study procedures. If at the time of the study, this information is known to be relevant to your medical care it will be given to the study doctor who will be encouraged to share it with you or your doctor. While you are in the study, however, the study site will not share certain new medical information about you that is created as part of the study (such as whether or not you are getting study drug, or the results of certain tests) unless the study doctor decides it is medically important to do so. This is done to stop the study results from being distorted. Once the study is over, you will be given access to medical information about you that you are entitled to see. You will be told if any of this medical information requires confirmation using a clinical test. This is important because some research results are for research purposes and may have only limited relevance for clinical diagnosis or treatment. At any time, you may ask your study doctor to let you see your personal information, e.g. name and address and to correct it if necessary. You may decide not to sign this authorization or you may cancel this authorization in writing at any time. Send your written withdrawal notice to: «FirstName» «MiddleName» «LastName» «Suffix» «Company» «Address» «SuiteDept» «City» «State» «Zip» However, you can only participate in the study if you authorize the use and disclosure of the information as described above.

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If you decide not to sign this authorization/consent form, you will not be enrolled in the study. If you sign this authorization and decide later to cancel this authorization, you will be withdrawn from the study at that time. Information collected up to the time you cancel this authorization will continue to be used as study data if it is scientifically appropriate to do so. If you withdraw from the study and withdraw your Authorization, no new information will be collected for study purposes unless the information concerns an adverse event (a bad effect) related to the study. If an adverse event occurs, your entire medical record may be reviewed. All information that has already been collected for study purposes, and any new information about an adverse event related to the study, will be sent to the study sponsor. If you withdraw from the study but do not withdraw your Authorization, new personal health information may be collected until this study ends. This Authorization does not have an expiration (ending) date.***will expire December 31, 2050. FOR WA sites*** If you do not withdraw this Authorization in writing, it will remain in effect indefinitely. Your study doctor will keep this Authorization for at least 6 years. If you do not sign this Authorization, you cannot participate in this research study or receive study-related treatment. If you withdraw this Authorization in the future, you will no longer be able to participate in this study. Your decision to withdraw your Authorization or not to participate will not involve any penalty or loss of access to treatment or other benefits to which you are entitled. What will GlaxoSmithKline (GSK) do with the information it gets? GSK may use the information that the study doctor gives it (i.e. the coded information): • • • •

•

By storing and analyzing it electronically to find out what this study is telling us By sharing it with regulatory authorities that approve new medicines, or with groups that check that research is done properly By publishing the results of the study (this will not include any information that directly identifies you) By sharing it as part of research with other companies or universities for the purpose of further understanding or developing this drug and with other GSK offices in this country and in other countries. If the information is sent to another country, GSK will apply the same level of protection to your information, to the extent permitted by local law By using it to plan new studies or other types of research or other medical purposes related to the development of the drug.

What will happen to tissue samples from this study? The blood samples collected in this study will not be labelled with information that directly identifies you, but a connection to your information will be kept. The blood samples are collected to establish your eligibility for participation in the study. Collected samples may be transferred to GlaxoSmithKline or other researchers working with GlaxoSmithKline.

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Do you have to stay in the study? Your participation in this study is voluntary. If you decide to take part, you will be given this information to keep and will be asked to sign this consent form. You may decline to take part in this study, or once in the study you may decide to discontinue participation at any time. You must inform your study doctor if you decide to discontinue study participation. The decision not to take part in the study or to stop participating in the study will not affect your current or future medical care, or any benefits to which you may otherwise be entitled. Contact your study doctor or clinic should you decide not to continue your participation in the study. He/she will explain the best way for you to discontinue your participation in the study. Who should you contact to answer any questions on the study? You have the right to ask the study doctor any questions concerning this study or about your participation in this research study at any time. If you have any questions about your participation in this research study, or if you feel that you have experienced a research-related injury or reaction to the study drug, contact: Principal Investigator:

«FirstName» «MiddleName» «LastName» «Suffix»

Daytime telephone number(s): «Phone» 24-hour contact number(s):

«Phone2»

If you have questions about your rights as a research subject, you may contact the (toll free). An Independent Review Board is a group of scientific and non-scientific individuals who perform the initial and ongoing ethical review of the research study with the study subject's safety and welfare in mind. If you have study-related comments, complaints or concerns, you should first contact the study investigator. Please call the IRB if you want to talk to someone other than the study investigator or have difficulty reaching the study investigator. For further information regarding the clinical trials process and your role as a research subject, you may visit the

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EXPERIMENTAL SUBJECT’S BILL OF RIGHTS Any person who is requested to consent to participate as a subject in a research study involving a medical experiment, or who is requested to consent on behalf of another, has the right to: 1.

Be informed of the nature and purpose of the experiment.

2.

Be given an explanation of the procedures to be followed in the medical experiment, and any drug or device to be used.

3.

Be given a description of any attendant discomforts and risks reasonably to be expected from the experiment.

4.

Be given an explanation of any benefits to the subject reasonably to be expected from the experiment, if applicable.

5.

Be given a disclosure of any appropriate alternative procedures, drugs or devices that might be advantageous to the subject, and their relative risks and benefits.

6.

Be informed of the avenues of medical treatment, if any, available to the subject after the experiment if complications should arise.

7.

Be given an opportunity to ask any questions concerning the experiment or the procedures involved.

8.

Be instructed that consent to participate in the medical experiment may be withdrawn at any time, and the subject may discontinue participation in the medical experiment without prejudice.

9.

Be given a copy of a signed and dated written consent form when one is required.

10.

Be given the opportunity to decide to consent or not to consent to a medical experiment without the intervention of any element of force, fraud, deceit, duress, coercion, or undue influence on the subject’s decision.

_____________________________________________________________________ Signature of Subject Date

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Subject’s Statement of Consent / Parent/Guardian Permission and Authorization A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) A Clinical Study to Test a Nasal Spray (fluticasone furoate nasal spray) for the Treatment of Perennial (year-round) Allergic Rhinitis □ □ □ □ □

I have read the statements in this informed consent form. I confirm that the study information and procedures have been explained to me by _______________________ during the consent process for this study. I have had the opportunity to ask questions about this study and that answers and explanations have been provided to me. I have been given time and opportunity to read the information carefully, to discuss it with others and to decide whether or not to take part in this study (or to give permission for my child to take part). I authorize the use and disclosure of my (or my child’s) personal health information as described above in this form. I have been told that by signing this form I am waiving protection offered by the HIPAA rule. I agree to take part in this study. / I give my permission for my child/ward to take part in this study.

Subject’s Signature

Date: DD/ MM/ YY

Printed name of Subject Parent/Guardian’s Signature Date: DD/ MM/ YY Printed Name of Parent/Guardian *Signature of Witness

Date: DD/ MM/ YY

*Printed name of Witness Signature of Person conducting Consent

Date: DD/ MM/ YY

Printed name of Person conducting Consent *If applicable

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Subject’s Statement of Assent (when subject is a minor) You are being asked to be in a research study. You do not have to be in this study. You may decide to participate or not. Even though your parents/guardians may say it is okay, you do not have to participate if you do not want to. If there is anything you do not understand about the study after reading this information, please ask your study doctor or study staff member. If you have not had a chance to speak with the study doctor or staff without your parent(s)/guardian(s) and would like to do so, please ask to speak with them alone. They will talk to you in private. If you do not want to be a part of this study, tell the study doctor or study staff and your doctor will keep taking care of you as s/he did before. You can stop being in this study any time for any reason. No one will be upset if you stop participating in this study or do not want to be in it. I agree to participate in this study.

Date:

Subject's Signature:

DD/MM/YY

Printed name of Subject:

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CONFIDENTIAL CONFIDENTIAL The GlaxoSmithKline group of companies

RM2008/00422/00 FFU111439

Division: World Wide Development Retention Category: GRS019 Information Type: Statistical Methods Appendix Title:

Statistical Methods Appendix for FFU111439: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR)

Compound Number: GW685698X Author’s Name, Title and Functional Area:

Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

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TABLE OF CONTENTS PAGE 1.

INTRODUCTION......................................................................................................4

2.

PRIMARY EFFICACY ANALYSIS ............................................................................4 2.1. PRIMARY EFFICACY ANALYSIS - SAS Output..........................................5

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ABBREVIATIONS ANCOVA CSR RAP rTNSS

Analysis of Covariance Clinical Study Report Reporting and Analysis Plan Reflective, Total Nasal Symptom Score

Trademark Information Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

None

SAS

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1.

INTRODUCTION

This document provides additional statistical details not included in the Reporting and Analysis Plan (RAP) or the main body of the Clinical Study Report (CSR) that will aid in the review of the data from study FFU111439.

2.

PRIMARY EFFICACY ANALYSIS

The primary efficacy endpoint was the mean change from baseline over the entire treatment period in daily, reflective total nasal symptom score (rTNSS), defined as the sum of the four individual nasal symptom scores of rhinorrhea, nasal congestion, nasal itching, and sneezing (each evaluated by the subject using a 4-point (0 to 3) categorical scale). The primary efficacy analysis method was the pairwise comparison of treatment groups (FF 110mcg versus placebo) using analysis of covariance (ANCOVA), with adjustments for baseline daily rTNSS, country, age, and gender, in addition to treatment effect. In the initial model fitting, a treatment-by-country interaction term was included in order to explore the uniformity of treatment effect across countries. The testing results (shown below) indicated that the interaction between treatment and country was not significant (see Section 2.1 for the SAS output). Variable in the Model Baseline daily rTNSS Age Gender Country Treatment Treatment-by-country

P-value 0.0002 0.2235 0.5958 0.0002 0.0220 0.8474

Testing results are displayed below for the main effects model (see Section 2.1 for the SAS output). Variable in the Model Baseline daily rTNSS Age Gender Country Treatment

P-value 0.0002 0.2223 0.5351 0.0002 0.0036

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FFU111439

2.1.

PRIMARY EFFICACY ANALYSIS - SAS Output PRIMARY EFFICACY ENDPOINT 1 MAIN EFFECTS MODEL 11:30 Thursday, September 4, 2008 The Mixed Procedure Model Information Data Set Dependent Variable Covariance Structure Estimation Method Residual Variance Method Fixed Effects SE Method Degrees of Freedom Method

WORK.DIARY NASSUM_C Diagonal REML Profile Model-Based Residual

Class Level Information Class

Levels

ATRTCD COUNTRY

2 7

SEX

2

Values FF 110mcg Placebo Canada Estonia Germany Hungary Russian Federati Slovakia United States F M

Dimensions Covariance Parameters Columns in X Columns in Z Subjects Max Obs Per Subject Observations Used Observations Not Used Total Observations

1 14 0 1 315 315 0 315

Covariance Parameter Estimates Cov Parm

Estimate

Residual

4.9711

Fit Statistics -2 Res Log Likelihood AIC (smaller is better) AICC (smaller is better) BIC (smaller is better)

5

5

1400.2 1402.2 1402.2 1405.9

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FFU111439 PRIMARY EFFICACY ENDPOINT 2 MAIN EFFECTS MODEL 11:30 Thursday, September 4, 2008 The Mixed Procedure Type 3 Tests of Fixed Effects

Effect ATRTCD COUNTRY NASSUM_B AGE SEX

Num DF

Den DF

F Value

Pr > F

1 6 1 1 1

304 304 304 304 304

8.62 4.61 14.48 1.50 0.39

0.0036 0.0002 0.0002 0.2223 0.5351

Estimates

Label PLAvsFF110

Estimate

Standard Error

DF

t Value

Pr > |t|

Alpha

0.7410

0.2524

304

2.94

0.0036

0.05

Estimates Label PLAvsFF110

Lower

Upper

0.2444

1.2377

Least Squares Means

Effect

Actual treatment code

Estimate

Standard Error

DF

t Value

Pr > |t|

ATRTCD ATRTCD

FF 110mcg Placebo

-3.1947 -2.4537

0.2337 0.2434

304 304

-13.67 -10.08

<.0001 <.0001

6

6

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FFU111439 PRIMARY EFFICACY ENDPOINT 3 TREATMENT BY INVESTIGATOR INTERACTION 11:30 Thursday, September 4, 2008 The Mixed Procedure Model Information Data Set Dependent Variable Covariance Structure Estimation Method Residual Variance Method Fixed Effects SE Method Degrees of Freedom Method

WORK.DIARY NASSUM_C Diagonal REML Profile Model-Based Residual

Class Level Information Class

Levels

ATRTCD COUNTRY

2 7

SEX

2

Values FF 110mcg Placebo Canada Estonia Germany Hungary Russian Federati Slovakia United States F M

Dimensions Covariance Parameters Columns in X Columns in Z Subjects Max Obs Per Subject Observations Used Observations Not Used Total Observations

1 28 0 1 315 315 0 315

Covariance Parameter Estimates Cov Parm

Estimate

Residual

5.0260

Fit Statistics -2 Res Log Likelihood AIC (smaller is better) AICC (smaller is better) BIC (smaller is better)

7

7

1386.2 1388.2 1388.3 1391.9

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FFU111439 PRIMARY EFFICACY ENDPOINT 4 TREATMENT BY INVESTIGATOR INTERACTION 11:30 Thursday, September 4, 2008 The Mixed Procedure Type 3 Tests of Fixed Effects

Effect

Num DF

Den DF

F Value

Pr > F

1 6 1 1 1 6

298 298 298 298 298 298

5.30 4.51 14.41 1.49 0.28 0.45

0.0220 0.0002 0.0002 0.2235 0.5958 0.8474

ATRTCD COUNTRY NASSUM_B AGE SEX ATRTCD*COUNTRY

Estimates

Label PLAvsFF110

Estimate

Standard Error

DF

t Value

Pr > |t|

Alpha

0.9419

0.4092

298

2.30

0.0220

0.05

Estimates Label PLAvsFF110

Lower

Upper

0.1367

1.7472

Least Squares Means

Effect

Actual treatment code

Estimate

Standard Error

DF

t Value

Pr > |t|

ATRTCD ATRTCD

FF 110mcg Placebo

-3.3061 -2.3642

0.2658 0.3192

298 298

-12.44 -7.41

<.0001 <.0001

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Table 1

Protocol Level Administration

Study Number: FFU111439

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) Data Management Group

1

GlaxoSmithKline

1

GCP Location of Study Master Regulatory inspection File

Address Address GSK Ware, UK

Name of Agency

GlaxoSmithKline None Records conducted Management, 5 Moore Drive Research Triangle Park, NC 27709 USA

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GlaxoSmithKline 5 Moore Drive Research Triangle Park,

Site of EU release

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Medical Site of Writing: Statistics Randomisation Manufacture Study Sponsor Group Clinical Report & Assembly Authorship Names of Company and Address Address Address Address authors and Address their Address Hamire Road Biostatistics and Biostatistics and Registration Respiratory GlaxoSmithKline Data Sciences, Data Sciences, and Medication Barnard Medicine GlaxoSmithKline Castle GlaxoSmithKline GlaxoSmithKline Ordering 1-3 Iron Bridge Development 1-3 Iron Bridge County 5 Moore Drive System 5 Moore Drive Rd Center (MDC) Rd Durham (RAMOS) Research Research GlaxoSmithKline Stockley Park Stockley Park Triangle Park, Pittsburgh Data UK Triangle Park, West 5 Moore Drive West DL12 8DT NC 27709 USA NC 27709 USA Center Uxbridge Research Uxbridge 4920 Middlesex Triangle Park, Middlesex Campbell’s Run NC 27709 USA UK UK Road, UB11 1BT UB11 1BT Pittsburgh, PA, 15205 USA Medical Writing: Protocol Authorship Names of authors and their Address

CONFIDENTIAL

Study Number: FFU111439

Study Sponsor

Medical Writing: Protocol Authorship 5 Moore Drive Research Triangle Park, NC 27709 USA

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) Statistics Group

Data Management Group

Medical Site of Site of Writing: EU Randomisation Manufacture Clinical Report release & Assembly Authorship NC 27709 USA

GCP Location of Study Master Regulatory inspection File

CONFIDENTIAL

2

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2

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Study Number: FFU111439

Participating Countries

Monitoring

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) Responsible for which sites

Sites of distribution in Europe

Laboratory Assessments

Audits Were Audits done?

Laboratory name and address

Centre Numbers

Canada

Canada:

Canada:

US & Canadian Sites: Quest Diagnostics Clinical Trials 7600 Tyrone Avenue Van Nuys CA 91405 USA

Estonia:

EU & Russian Sites: Quest Diagnostics Clinical Trials Unit B1, Parkway West Crawford Lane, Heston, Middlesex TWA 9QA, UK

Estonia

Estonia: GSK Export Branch Office Parnu Road 67a 10134 Tallinn Estonia

3

yes/no

Centre numbers

Name and address of audit group

No

CONFIDENTIAL

3

GSK 7333 Mississauga Rd. Mississauga, Ontario L5N 6L4, Canada

Address

Conducted by:

GSK Clinical Trial Supplies GSK R&D Ltd New Frontiers Science Park (South) Third Avenue Harlow Essex CM19 5AW UK

No

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Country Name

Address of resource

Centre Number of Site(s)

CONFIDENTIAL

Study Number: FFU111439

Participating Countries

Monitoring

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) Responsible for which sites

Sites of distribution in Europe

Laboratory Assessments

Audits Were Audits done?

Laboratory name and address

Germany

Germany:

Germany:

EU & Russian Sites: Quest Diagnostics Clinical Trials Unit B1, Parkway West Crawford Lane, Heston, Middlesex TWA 9QA, UK

Hungary:

EU & Russian Sites: Quest Diagnostics Clinical Trials Unit B1, Parkway West Crawford Lane, Heston, Middlesex TWA 9QA, UK

4

GSK Alsterufer 1 20354 Hamburg, Germany

Hungary

Hungary: GSK Csorsz u.43. Budapest 1124 Hungary

4

Address

yes/no

GSK Clinical Trial Supplies GSK R&D Ltd New Frontiers Science Park (South) Third Avenue Harlow Essex CM19 5AW UK GSK Clinical Trial Supplies GSK R&D Ltd New Frontiers Science Park (South) Third Avenue Harlow Essex CM19 5AW UK

No

Centre numbers

Name and address of audit group

No

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Centre Numbers

Conducted by:

CONFIDENTIAL

Country Name

Address of resource

Centre Number of Site(s)

CONFIDENTIAL

Study Number: FFU111439

Participating Countries

Monitoring

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) Responsible for which sites

Sites of distribution in Europe

Laboratory Assessments

Audits Were Audits done?

Laboratory name and address

Russian Federation

Russian Federation:

Russian Federation:

EU & Russian Sites: Quest Diagnostics Clinical Trials Unit B1, Parkway West Crawford Lane, Heston, Middlesex TWA 9QA, UK

Slovakia:

EU & Russian Sites: Quest Diagnostics Clinical Trials Unit B1, Parkway West Crawford Lane, Heston, Middlesex TWA 9QA, UK

5

ZAO GSK Trading 17 Krylatskaya str., 121614 Moscow, Russia

Slovakia

Slovakia: GSK Slovakia s.r.o. Galvaniho 7/A 821 04, Bratislava Slovak Republic

5

Address

yes/no

GSK Clinical Trial Supplies GSK R&D Ltd New Frontiers Science Park (South) Third Avenue Harlow Essex CM19 5AW UK GSK Clinical Trial Supplies GSK R&D Ltd New Frontiers Science Park (South) Third Avenue Harlow Essex CM19 5AW UK

No

Centre numbers

Name and address of audit group

No

RM2008/00422/00

Centre Numbers

Conducted by:

CONFIDENTIAL

Country Name

Address of resource

Centre Number of Site(s)

CONFIDENTIAL

Study Number: FFU111439

Participating Countries

Monitoring

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Once-Daily Intranasal Administration of Fluticasone Furoate Nasal Spray 110mcg in Adult and Adolescent Subjects 12 years of Age and Older with Perennial Allergic Rhinitis (PAR) Responsible for which sites

Sites of distribution in Europe

Laboratory Assessments

Audits Were Audits done?

Country Name

6

United States: US Monitoring GSK 2301 Renaissance King of Prussia, PA 19406 USA

Centre Numbers United States:

Laboratory name and address

Address

US & Canadian Sites: Quest Diagnostics Clinical Trials 7600 Tyrone Avenue Van Nuys CA 91405 USA

yes/no

Centre numbers

Conducted by: Name and address of audit group

No

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United States of America (USA)

Address of resource

Centre Number of Site(s)

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6

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